American Journal of Epidemiology
Copyright ª 2006 by the Johns Hopkins Bloomberg School of Public Health
All rights reserved; printed in U.S.A.
Vol. 164, No. 7
DOI: 10.1093/aje/kwj260
Advance Access publication August 18, 2006
Original Contribution
A Population-based Ecologic Study of Inflammatory Bowel Disease: Searching
for Etiologic Clues
Chris Green1,2, Lawrence Elliott2, Carole Beaudoin1,2, and Charles N. Bernstein3,4
1
Public Health Branch, Manitoba Health, Winnipeg, Manitoba, Canada.
Department of Community Health Sciences, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
3
Department of Internal Medicine, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
4
Inflammatory Bowel Disease Clinical and Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg,
Manitoba, Canada.
2
Received for publication April 14, 2005; accepted for publication August 9, 2005.
The authors’ objective in this study was to determine geographic variations in the incidence of inflammatory
bowel disease (IBD), specifically Crohn’s disease and ulcerative colitis, in the Canadian province of Manitoba and
its association with the sociodemographic, geographic, and disease-related characteristics of the study population.
Using the University of Manitoba IBD Epidemiology Database, the authors applied spatial and ecologic techniques
to visualize, explore, and model the incidence of Crohn’s disease and ulcerative colitis for the period 1990–2001.
The study demonstrated marked, statistically significant geographic variability in rates of both Crohn’s disease and
ulcerative colitis associated with the characteristics of the study population. Incidences of Crohn’s disease and
ulcerative colitis were observed to be highest among non-Aboriginal persons, persons of high socioeconomic
status, persons with the lowest rates of enteric infection, and persons with the highest rates of multiple sclerosis.
The observation of an inverse association between IBD incidence and rates of reportable enteric infection at the
population level is consistent with the ‘‘hygiene hypothesis,’’ which suggests that early exposure to enteric agents
affords protection against eventual development of IBD. The positive association between IBD incidence rates and
multiple sclerosis suggests that these two chronic, immunologically mediated diseases may have a common
environmental etiology. This study underscores the importance of environment in IBD causation.
colitis, ulcerative; Crohn’s disease; inflammatory bowel disease; multiple sclerosis
Abbreviations: CI, confidence interval; IBD, inflammatory bowel disease; IRR, incidence rate ratio.
Editor’s note: An invited commentary on this article
appears on page 624, and the authors’ response appears on
page 627.
variation in IBD incidence suggests that extrinsic environmental factors acting at the population level may be involved
in its pathogenesis. Since the mid-1900s, the incidence of
IBD has been observed to be rapidly increasing in Northern
European and North American populations (1, 2). In addition, significant geographic variations in IBD incidence have
been observed in the United States, Norway, and Canada.
Older studies have suggested that IBD occurs more
frequently in populations of high socioeconomic status
(3, 4). Recently, in Manitoba, Canada, using different
While the causes of inflammatory bowel disease (IBD) are
unknown, there is evidence that the condition is immunologically mediated and that genetic factors may play an important role in its etiology. Significant temporal and geographic
Correspondence to Dr. Charles N. Bernstein, Faculty of Medicine, University of Manitoba, 804F-715 McDermot Avenue, Winnipeg, Manitoba,
Canada R3E-3P4 (e-mail: [email protected]).
615
Am J Epidemiol 2006;164:615–623
616 Green et al.
population-based approaches, Blanchard et al. (5) found
IBD to be associated with a slightly higher socioeconomic
status (5), and using other analysis strategies, Bernstein
et al. (6) found no difference in socioeconomic status compared with controls. As the prevalence of IBD increases, it
will be important to reassess its association with socioeconomic status in the context of other possibly related variables. Previously, IBD has been associated with Jewish
ethnicity and has been observed less frequently in minority
populations and in populations exposed to high levels of
enteric infection in early childhood (1, 5, 7). It is important
to try to better understand how variations in population-level
characteristics across time and space may be affecting the
trajectory of IBD.
In this report, we build upon recent work undertaken to
document and model rates of IBD in the Canadian province
of Manitoba. Employing updated data and more advanced
geographic methods, we used the University of Manitoba
IBD Epidemiology Database to refine initial descriptions
of population-level variations in IBD in Manitoba and the
sociodemographic, ethnic, and environmental factors associated with these variations. Additionally, we examined
whether IBD incidence covaries at the population level with
the incidence of multiple sclerosis, a chronic, immunologically mediated disease that shares temporal phenotypic and
immunopathogenetic similarities with IBD.
MATERIALS AND METHODS
Study setting
The study was conducted in the central Canadian province of Manitoba. Manitoba has a population of 1.1 million
people, and more than 50 percent (n ¼ 645,000) reside in the
City of Winnipeg, the provincial capital (8). The majority of
Manitobans are of European descent, whereas 10 percent of
the population is self-identified as having Aboriginal ancestry. Manitoba has a universal health insurance plan, and all
residents of the province are eligible to receive health-care
services with no payment required at the time of service.
Data sources
The IBD data used for this study were obtained from the
University of Manitoba IBD Epidemiology Database, which
has been described in detail previously (9). For the purposes
of this study, only incident and prevalent cases of IBD for
the years 1990–2001 inclusive were used.
The ecologic measure of socioeconomic status used in the
study was created by combining small-area estimates from
the 2001 Census Canada micro-data files (8) for average
family income, unemployment rate, and percentage of the
adult population with some postsecondary education. The
resulting composite index, known as the Socio-Economic
Status Index, was generated using the SIG-EPI program
(10), version 1.030, with standardized z scores and equal
weights attributed to each variable. Three ecologic measures
of ethnicity—the percentage of the population reporting
Jewish ethnicity, the percentage of the population reporting
Aboriginal ancestry, and the percentage of the population
reporting ‘‘visible minority’’ status—were also obtained
from the 2001 Census Canada micro-data files (‘‘visible minorities’’ are defined as persons, other than Aboriginal peoples, who are non-Caucasian in race or non-White in color).
Small-area estimates of the age-standardized enteric infection incidence rate (the combined incidence of all cases of
reportable enteric disease, the most frequent being campylobacteriosis, salmonellosis, shigellosis, and giardiasis) from
1996–2001 were obtained from the Public Health Branch of
Manitoba Health, and small-area estimates of multiple sclerosis incidence rates for 1989–1998 were obtained from
a multiple sclerosis surveillance database recently developed
at the Public Health Branch of Manitoba Health (11).
The ‘‘urban residence’’ designation was assigned to persons living in the City of Winnipeg, the only urban center in
Manitoba with a population greater than 50,000 (8). The
‘‘on-reserve’’ designation was assigned to persons living
in one of the 61 First Nations reserve communities scattered
throughout rural Manitoba.
Assessment of time trends
For assessment of temporal trends in IBD, age-standardized
annual incidence and prevalence rates were calculated for the
years 1990–2001. Annual incidence rates were calculated
using the midyear population at risk based on the Manitoba
population registry. Annual prevalence rates were calculated
on June 15 of each year using the midyear population at risk.
Directly age-adjusted rates were calculated using the 1996
Manitoba population as the standard.
Spatial methods
Records in the University of Manitoba IBD Epidemiology
Database were geocoded to neighborhoods in the City of
Winnipeg (n ¼ 230) using postal codes and to health municipalities in rural areas of Manitoba (n ¼ 268) using the
Manitoba Health municipal code recorded in the health record. The resulting set of 498 geographic areas had an average
population size of 2,000. Spatial analysis of the data was
undertaken in three steps according to the three-component
framework proposed by Gatrell and Bailey (12).
In the first step, data visualization, directly age-standardized
Crohn’s disease and ulcerative colitis incidence rates for
1990–2001 combined were estimated for each of 498 geographic areas. To control for unstable rate estimates resulting from small case counts, stable rate estimates were
generated by means of an adaptive mean nearest-neighbor
smoothing algorithm, using a program written in Epi Info,
version 6.04d (13). This program uses a spatial weights table
calibrated to the population size of each geographic area
and its first-, second-, and third-order neighbors. Data for
geographic areas with a population under 10,000 were
smoothed by adaptively borrowing both numerator and denominator data from neighboring geographic areas to the
degree required to generate a denominator of approximately
constant size (10,000 persons). Directly standardized rates
using the 1996 general Manitoba population at risk as the
standard were calculated using the borrowed data. Thematic
Am J Epidemiol 2006;164:615–623
An Ecologic Study of Inflammatory Bowel Disease
617
300
250
Cases/100,000
Crohn’s disease prevalence
200
150
164.6
177.6
190.1
198.6
208.4
216.8
13.91
12.62
225.4
236.9
248.8
255.8
261.5 269.7
16.64
12.57
15.12 13.65
100
50
0
Crohn’s disease incidence
15.24
1990
15.9
1991
14.53
1992
14.64
1993
1994
1995
14.85
1996
18.24
1997
1998
1999
2000
2001
Year
300
Cases/100,000
250
200
150
UC prevalence
143.3
154.5
162.7
173.2
187.6
198.7
207.8
222.9
230.6
236.2 240.9
216.2
14.31
15.3
14.05
13.77 10.52
100
50
UC incidence
16.19
0
1990
13.4
1991
13.6
1992
17.8
1993
18.15
1994
15.24
1995
12.58
1996
1997
1998
1999
2000
2001
Year
FIGURE 1. Prevalence and incidence (number of cases per 100,000 population) of Crohn’s disease (top) and ulcerative colitis (UC) (bottom) in
Manitoba, Canada, 1990–2001. Results were age-standardized to the 1996 Manitoba population.
maps of standardized rates were produced for both Crohn’s
disease and ulcerative colitis.
In the second step, data exploration, the spatial scan statistic was used to confirm that disease patterns identified at
the data visualization stage were not due to random spatial
variation. This statistic, which identifies high- and low-rate
cluster areas through the aggregation of contiguous geographic regions, was calculated using SaTScan, version
2.1 (14). The software was set to find age-adjusted clusters
with a maximum size of 50 percent of the study population,
and detected clusters were tested for significance using 999
Monte Carlo random simulations. The program assumes
a Poisson distribution and calculates indirectly standardized
rates (expressed as the relative risk, which is the observed
rate divided by the expected rate) for each identified geographic cluster. Only clusters significant at the p < 0.05
level were retained for mapping. The specifics of the spatial
scan statistic have been described elsewhere (15).
In the third step, data modeling, the composite measure of
socioeconomic status (Socio-Economic Status Index) and
the ethnicity- and disease-related characteristics (enteric infections, multiple sclerosis) associated with each of the 498
geographic study areas were classified into tertiles. These
were assigned to the individual IBD records in the database.
Am J Epidemiol 2006;164:615–623
Using the Poisson regression functionality in NCSS 2001
(16), incidence rate ratios adjusted for age and gender were
then calculated for each predictor variable. Ninety-five percent confidence intervals were calculated and corrected for
model overdispersion using the phi multiplier function in
NCSS.
RESULTS
Temporal trends
The age-adjusted incidence of Crohn’s disease remained
relatively constant between 1990 and 2001, decreasing
slightly from 15.24 cases/100,000 population in 1990 to
13.65 cases/100,000 population in 2001 (figure 1, top).
The average incidence rate during the study period was
14.8 cases/100,000 population. In 1990, there were 176 incident cases of Crohn’s disease, a number which decreased
to 157 by 2001. The age-adjusted prevalence of Crohn’s
disease increased significantly during the study period, from
164.6 cases/100,000 population in 1990 to 269.7 cases/
100,000 population in 2001 (figure 1, top). The average
cumulative prevalence rate during the study period was
222.2 cases/100,000 population. In 1990, there were 1,848
618 Green et al.
prevalent cases of Crohn’s disease; the number had increased to 3,140 by 2001.
The age-adjusted incidence of ulcerative colitis decreased
between 1990 and 2001, from 16.19 cases/100,000 population in 1990 to 10.52 cases/100,000 population in 2001
(figure 1, bottom). The average incidence rate during the
study period was 14.6 cases/100,000 population. In 1990,
there were 181 incident cases of ulcerative colitis, a number
which decreased to 123 by 2001. The age-adjusted prevalence of ulcerative colitis increased significantly during the
study period, from 143.3 cases/100,000 population in 1990
to 240.9 cases/100,000 population in 2001 (figure 1, bottom). The average cumulative prevalence rate during the
study period was 197.9 cases/100,000 population. In 1990,
there were 1,581 prevalent cases of ulcerative colitis; the
number had increased to 2,846 by 2001.
Data visualization
The thematic maps of Crohn’s disease and ulcerative colitis incidence (figure 2) show that there is marked geographic variability in the rates of both diseases across the
province of Manitoba. Regionally, Crohn’s disease incidence rates range from <7.6 cases/100,000 population in
the northern regions of the province and in the central core
of the City of Winnipeg to as high as 28.07 cases/100,000
population in the outer suburbs of Winnipeg and in the
southwestern corner of the province. Regional ulcerative
colitis incidence shows similar patterns, with rates ranging
from <9.9 cases/100,000 population in the north of the
province and in the Winnipeg core to as high as 29.47
cases/100,000 population in the southwestern suburbs of
Winnipeg and southwestern Manitoba.
Data exploration
The spatial scan statistic identified statistically significant
high- and low-rate clusters of Crohn’s disease and ulcerative
colitis incidence in most of the same geographic areas as
those identified as high- and low-risk areas on the thematic
maps (figure 3). High-rate clusters of both Crohn’s disease
and ulcerative colitis incidence with relative risks greater
than 1 were identified in Winnipeg suburbs and southwestern Manitoba (relative risks ranged from 1.3 to 2.9);
low-rate clusters of Crohn’s disease and ulcerative colitis
incidence with relative risks less than 1 were observed in
the central core of Winnipeg and in southern Manitoba (relative risks ranged from 0.37 to 0.54). A low-rate cluster in
northern Manitoba was identified only for Crohn’s disease
(relative risk ¼ 0.645). This confirms that there is nonrandom clustering of Crohn’s disease and ulcerative colitis
events across the province and suggests that the marked
spatial patterns in incidence observed in the thematic maps
are unlikely to have occurred by chance alone.
Data modeling
Table 1 shows that for both Crohn’s disease and ulcerative
colitis, age- and gender-adjusted incidence rates are strongly
graded by the individual, geographic, socioeconomic, and
disease-related variables used in this study. Compared with
the lowest reference quantile, the incidence of Crohn’s disease was observed to be highest in females (incidence rate
ratio (IRR) ¼ 1.37, 95 percent confidence interval (CI):
1.24, 1.50) and in the age group 20–29 years (IRR ¼ 3.78,
95 percent CI: 3.27, 4.37). After adjustment for age and sex,
Crohn’s disease incidence was also observed to be highest in
urban areas (IRR ¼ 1.29, 95 percent CI: 1.17, 1.41), offreserve locations (IRR ¼ 11.07, 95 percent CI: 4.81, 25.45),
populations with the highest level of socioeconomic status
(IRR ¼ 1.77, 95 percent CI: 1.55, 2.02), the lowest percentage of the population reporting an Aboriginal background
(IRR ¼ 5.47, 95 percent CI: 3.37, 8.87), the highest percentage of the population reporting Jewish ethnicity (IRR ¼
1.52, 95 percent CI: 1.22, 1.89), persons with the lowest
rates of enteric infection (IRR ¼ 1.52, 95 percent CI:
1.31, 1.78), and persons with the highest rates of multiple
sclerosis (IRR ¼ 2.90, 95 percent CI: 2.19, 3.85). The relation of Crohn’s disease incidence to visible minority status
was ambiguous, with the highest rate being observed in the
middle tertile (IRR ¼ 1.26, 95 percent CI: 1.08, 1.46). The
relations between ulcerative colitis incidence and predictor
variables were similar in direction to those observed with
Crohn’s disease and were all statistically significant at the
p < 0.05 level. The relation between ulcerative colitis and
predictor variables tended to be weaker, however, as evidenced by smaller incidence rate ratios.
DISCUSSION
In this paper, we have described the temporal and spatial
variation in Crohn’s disease and ulcerative colitis in Manitoba, Canada, for 1990–2001. Despite a constant or slightly
decreasing incidence rate, the prevalences of both Crohn’s
disease and ulcerative colitis in Manitoba are continuing to
increase, since new cases continue to arise, particularly
among young adults.
Thematic maps have shown a pronounced geographic
concentration of both Crohn’s disease and ulcerative colitis
incidence in the outer suburbs of Winnipeg and in southwestern Manitoba. The spatial scan statistic results suggest
that these observed spatial patterns are real and are unlikely
to have occurred by chance alone. The existence of true
population-level variability in Crohn’s disease and ulcerative colitis incidence is further confirmed by the observation
of a strong and significant grading of both Crohn’s disease
and ulcerative colitis incidence rates by a number of geographic, individual, sociodemographic, ethnic, and diseaserelated predictor variables. We also found that there appears
to be a high degree of spatial covariation between Crohn’s
disease and ulcerative colitis. This covariation is not surprising, given that when IBD (either Crohn’s disease or ulcerative colitis) occurs in families, first-degree relatives of the
proband with IBD are increasingly likely to contract either
Crohn’s disease or ulcerative colitis (17).
We found a positive association of both Crohn’s disease
and ulcerative colitis with higher socioeconomic status, paralleling our findings in a previous ecologic study (5). This
observation is consistent with the ‘‘hygiene hypothesis,’’
Am J Epidemiol 2006;164:615–623
An Ecologic Study of Inflammatory Bowel Disease
619
FIGURE 2. Incidence (number of cases per 100,000 population) of Crohn’s disease (top) and ulcerative colitis (bottom) in the province of
Manitoba and the City of Winnipeg, Manitoba, Canada, 1990–2001. Results were age-standardized to the 1996 Manitoba population.
which suggests that persons with higher living standards
may be protected from childhood infections because of
cleaner environments and smaller households but are more
Am J Epidemiol 2006;164:615–623
susceptible to chronic intestinal inflammation in adulthood
as a result of responding to infectious agents later in life
(18, 19).
620 Green et al.
FIGURE 3. Incidence analysis of Crohn’s disease (top) and ulcerative colitis (bottom) in the province of Manitoba and the City of Winnipeg
carried out using the spatial scan statistic, Manitoba, Canada, 1990–2001. The maximum cluster was set at 50% of the study population.
The hygiene hypothesis is further supported by the observation in this study of an inverse relation between IBD and
rates of reportable enteric infection at the ecologic level.
This observation conflicts with other studies, which have
shown at the individual level a higher frequency of gastro-
enteritis or diarrheal illness during infancy or perinatal infections among future IBD patients (20, 21). Recall bias
may be a limitation of these studies (20). However, these
studies raise the possibility that there may be important
differences as to the timing of infection in childhood when
Am J Epidemiol 2006;164:615–623
An Ecologic Study of Inflammatory Bowel Disease
TABLE 1. Results from Poisson regression analysis of the
incidence of inflammatory bowel disease in Manitoba, Canada,
1990–2001
Crohn’s disease
IRR*
95% CI*
IRR
95% CI
Age group (years)
0–19 (reference)
1.0
20–29
3.78
30–39
2.55
2.19, 2.97
5.33
4.91
0.94, 1.39
1.32
1.13, 1.53
4.22, 5.71
1.52
1.22, 1.89
1.45
1.21, 1.74
4.38
3.77, 5.09
1.26, 1.74
4.73
4.09, 5.48
Gender
1.0
1.11
1.02, 1.20
Urbanicity of
residencey
Rural (reference)
1.0
Urban
1.29
1.12
1.04, 1.21
Residence on a
First Nations
reservey
On reserve
(reference)
Off reserve
1.0
11.07
1.0
4.81, 25.45
1.96
1.0
Member of a visible
minorityy,§ (% of
population)
18.53–47.6
(reference)
1.0
5.62–18.52
1.26
1.08, 1.46
1.30
1.14, 1.47
0–5.58
1.06
0.92, 1.22
1.23
1.10, 1.39
1.0
Enteric infections
1996–2001y
(cases/10,000){
1.0
1.17, 1.41
95% CI
1.14
1.68, 2.29
1.24, 1.50
IRR
12.07–29.17
1.48
1.37
95% CI*
3.58–12.06
1.96
Female
IRR*
Self-reported Jewish
ethnicityy (% of
population)
4.58, 6.20
55
1.0
Ulcerative colitis
1.0
40–54
Male (reference)
Crohn’s disease
Predictor
0–3.57 (reference)
1.0
3.27, 4.37
TABLE 1. Continued
Ulcerative colitis
Predictor
621
1.47, 2.62
Socio-Economic
Status Indexy,z
Low (reference)
1.0
1.0
Medium
1.59
1.38, 1.82
1.13
1.02, 1.26
High
1.77
1.55, 2.02
1.48
1.34, 1.63
11.087–37.804
(reference)
1.0
6.01–11.013
1.50
1.28, 1.75
1.27
1.13, 1.43
1.79–5.97
1.52
1.31, 1.78
1.19
1.06, 1.33
1.0
Multiple sclerosis
1989–1998y
(cases/10,000)#
0–0.440 (reference)
1.0
0.446–1.077
2.21
1.67, 2.93
1.39
1.0
1.15, 1.68
1.078–1.90
2.90
2.19, 3.85
1.80
1.49, 2.17
Table continues
* IRR, incidence rate ratio; CI, confidence interval.
y Adjusted for age and gender.
z A composite index of socioeconomic status generated from
average family income, unemployment rate, and educational level
(see Materials and Methods).
§ ‘‘Visible minorities’’ are defined as persons, other than Aboriginal
peoples, who are non-Caucasian in race or non-White in color.
{ Number of cases of enteric infection/10,000 population during
the period 1996–2001.
# Number of incident cases of multiple sclerosis/10,000 population
during the period 1989–1998.
infections are contracted. Infections acquired during the immediate perinatal period or early infancy may establish aberrant immune responses to microbes encountered at a later
time, while early- to mid-childhood infections may promote
tolerance to like organisms. The nature of our study did not
allow assessment of the relation between age of enteric infection and development of IBD, but this could be important
prospective, population-based research to pursue.
A First Nations community in Manitoba has been found
to be ubiquitously infected with Helicobacter pylori, even at
very young ages (22, 23). H. pylori infection has been associated with poorer domestic hygiene. The Manitoba Aboriginal population, even when living in the major urban
area of the province, retains low rates of IBD. It is possible
that the low rates of IBD observed in the core of Winnipeg
may be the result of the high concentration of Aboriginal
people living in that area who migrated there from remote
reserve communities, bringing with them decreased susceptibility to IBD. For the Aboriginal population, there may be
a genetic inability to mount an aberrant immune response to
the microbe(s) that may cause IBD. Alternatively, earlier
infections or contact with microbes through less-hygienic
living conditions might promote tolerance to offending microbes later in life.
The most novel finding of interest is the significant association between areas with a high incidence of IBD and
areas with a high incidence of multiple sclerosis. We have
recently found that rates of multiple sclerosis are significantly higher among subjects with ulcerative colitis than
among controls (24). Multiple sclerosis, like IBD, is thought
to possibly be a complex T-cell-mediated disorder (25). Perhaps multiple sclerosis and IBD share similar etiologies,
with persons genetically programmed to respond with either
gut inflammation or neural inflammation. Multiple sclerosis,
Self-reported
Aboriginal
statusy (% of
population)
61.9–99.23
(reference)
1.0
19.18–61.8
3.20
1.92, 5.34
1.60
1.22, 2.09
0–19.17
5.47
3.37, 8.87
1.99
1.55, 2.55
1.0
Am J Epidemiol 2006;164:615–623
622 Green et al.
like IBD, is associated with a high rate of affected firstdegree relatives (26). Regions of overlap upon chromosomal
analysis of susceptibility loci have been found for a number
of autoimmune diseases, including multiple sclerosis and
Crohn’s disease (27). This nonrandom clustering supports
the notion that susceptibility to clinically distinct autoimmune diseases may be influenced by a common set of genes
(28). Much as the NOD-2 gene, which encodes for a protein
in gut antigen-presenting cells that triggers a cellular response to bacteria, is associated with Crohn’s disease (29,
30), perhaps genetic mutations in multiple sclerosis will be
proven to be associated with myelin antigen-presenting
cells, which might be proven to respond to the same microbes that trigger Crohn’s disease.
Previous epidemiologic reviews of IBD have suggested
a gradient reflecting higher rates in northern climates than in
southern ones (31–34), although the emergence of higher
incidence rates in Southern Europe has led to questioning of
this gradient (35). The high Manitoba incidence rates, which
are the highest incidence rates yet reported for Crohn’s disease, may fit with a northern predilection for this disease.
Recently, it was proposed that refrigeration and proliferation
of psychrotropic bacteria might be responsible for the upswing in Crohn’s disease in developed nations during the
latter half of the 20th century (36). Perhaps these high rates,
well spread out across Manitoba, suggest that organisms that
survive cold well should be studied further.
This study had a number of methodological limitations
that must be kept in mind when interpreting its results. First,
the incidence rates were generated from data derived from
administrative databases. However, a previous study evaluated the accuracy of this approach and found high specificity
in comparison with detailed chart review (9). Secondly, we
used an ecologic analysis. Indicators of socioeconomic status, ethnicity, and disease exposure were measured for one
time period at the geographic level, since data on these
factors were not available longitudinally in individual health
records. The ecologic design has been considered weak for
applying characteristics of a geographic area to individuals
living within that area (37). However, recent work by Rose
(38), Krieger et al. (39, 40), and Mustard et al. (41) has highlighted the important and independent effect that populationlevel factors have on the health of individuals. In our study,
the ecologic predictor estimates that were applied to individual cases of Crohn’s disease were generated from a set of
spatial units with an average population size of only 2,000
persons, minimizing the possibility of significant heterogeneity within those geographic areas.
In conclusion, this study has illustrated the power of having accurate population-based information on the epidemiology of IBD in Manitoba. Through the application of spatial
and ecologic methods, we have demonstrated substantial
clustering and small-area variations in the incidence of
IBD and have shown that these variations are associated
with the socioeconomic, ethnic, geographic, and diseaserelated characteristics of the study population. The results
of this study provide strong evidence that the causes of IBD
are environmental in nature and suggest that further work in
modeling the relation of IBD to environmental determinants
is warranted.
ACKNOWLEDGMENTS
Dr. Charles Bernstein is supported in part by a Canadian
Institutes of Health Research Investigator Award and by
a Crohn’s and Colitis Foundation of Canada Research
Scientist Award.
Conflict of interest: none declared.
REFERENCES
1. Bernstein CN, Blanchard JF. Epidemiology of inflammatory
bowel disease. In: Cohen RD, ed. Inflammatory bowel disease:
diagnosis and therapeutics. Totowa, NJ: Humana Press, Inc,
2003:17–32.
2. Loftus EV Jr. Clinical epidemiology of inflammatory bowel
disease: incidence, prevalence, and environmental influences.
Gastroenterology 2004;126:1504–1.
3. Bonnevie O. A socioeconomic study of patients with ulcerative
colitis. Scand J Gastroenterol 1967;2:129–36.
4. Keighley A, Miller DS, Hughes AO, et al. The demographic
and social characteristics of patients with Crohn’s disease
in the Nottingham area. Scand J Gastroenterol 1976;11:
293–6.
5. Blanchard JF, Bernstein CN, Wajda A, et al. Small-area variations and socio-demographic correlates for the incidence of
Crohn’s disease and ulcerative colitis. Am J Epidemiol 2001;
154:328–35.
6. Bernstein CN, Kraut A, Blanchard JF, et al. The relationship
between inflammatory bowel disease and socioeconomic variables. Am J Gastroenterol 2001;96:2117–25.
7. Wells RW, Blennerhassett MG. The increasing prevalence
of Crohn’s disease in industrialized societies: the price of
progress? Can J Gastroenterol 2005;19:89–95.
8. Statistics Canada. Profile for Canada, provinces, territories,
census divisions, census subdivisions and dissemination areas,
2001 census. Cumulative electronic components of profiles,
2001 census. (CD-ROM). (Catalogue no.
95F0495XCB2001002). Ottawa, Ontario, Canada: Statistics
Canada, 2003. (http://www.statcan.ca/bsolc/english/bsolc?
catno¼95F0495XCB2001002).
9. Bernstein CN, Blanchard JF, Rawsthorne P, et al. Epidemiology of Crohn’s disease and ulcerative colitis in a central
Canadian province: a population-based study. Am J Epidemiol
1999;149:916–24.
10. Health Analysis and Information Systems Area, Pan American
Health Organization. Sistema de Información Geográfica en
Epidemiologı́a y Salud Pública. (In Spanish). Washington,
DC: Pan American Health Organization, 2004. (http://ais.
paho.org/sigepi/index.htm?xml¼sigepi/index.htm).
11. Elliott LJ, Yu N, Melanson M, et al. Application of a validated method using medical claims data to demonstrate very
high prevalence and incidence of multiple sclerosis in a
Canadian province. (Abstract 232). Am J Epidemiol 2004;
159(suppl):S58.
12. Gatrell AC, Bailey TC. Interactive spatial data analysis in
medical geography. Soc Sci Med 1996;42:843–55.
13. Centers for Disease Control and Prevention. Epi Info 6.
Atlanta, GA: Centers for Disease Control and Prevention,
2001. (http://www.cdc.gov/epiinfo/Epi6/ei6.htm).
14. Kulldorff M. SaTScan: software for the spatial, temporal,
and space-time scan statistics. Silver Spring, MD: Information Management Services, Inc, 2005. (http://www.
satscan.org/).
Am J Epidemiol 2006;164:615–623
An Ecologic Study of Inflammatory Bowel Disease
15. Kulldorff M, Feuer EJ, Miller BA, et al. Breast cancer clusters
in the northeast United States: a geographic analysis. Am J
Epidemiol 1997;146:161–70.
16. Hintz J. NCSS: statistical and power analysis software.
Kaysville, UT: NCSS, 2001. (http://www.ncss.com/).
17. Yang H-Y, McElree C, Shanahan F, et al. Familial empirical
risks for inflammatory bowel disease: differences between
Jews and non-Jews. Gut 1993;34:517–24.
18. Gent AE, Hellier MD, Grace RH, et al. Inflammatory bowel
disease and domestic hygiene in infancy. Lancet 1994;343:
766–7.
19. MacDonald TT. Breakdown of tolerance to the intestinal
bacterial flora in inflammatory bowel disease (IBD). Clin Exp
Immunol 1995;102:445–7.
20. Whorwell PJ, Holdstock G, Whorwell GM, et al. Bottle
feeding, early gastroenteritis, and inflammatory bowel disease.
Br Med J 1979;1:382.
21. Ekbom A, Adami HO, Helmick CG, et al. Perinatal risk factors
for inflammatory bowel disease: a case-control study. Am J
Epidemiol 1990;132:1111–19.
22. Bernstein CN, McKeown I, Embil JM, et al. Seroprevalence of
Helicobacter pylori, incidence of gastric cancer, and peptic
ulcer-associated hospitalizations in a Canadian Indian population. Dig Dis Sci 1999;44:668–74.
23. Sinha SK, Martin B, Sargent M, et al. Age at acquisition of
Helicobacter pylori in a paediatric Canadian First Nations
population. Helicobacter 2002;7:76–85.
24. Bernstein CN, Wajda A, Blanchard JF. The clustering of other
chronic inflammatory diseases in inflammatory bowel disease:
a population-based study. Gastroenterology 2005;129:827–36.
25. Sospedra M, Martin R. Immunology of multiple sclerosis.
Annu Rev Immunol 2004;23:683–747.
26. Ebers GC, Sadovnick AD. The role of genetic factors in
multiple sclerosis susceptibility. J Neuroimmunol 1994;54:
1–17.
27. Becker KG, Simon RM, Bailey-Wilson JE, et al. Clustering of
non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci
U S A 1998;95:9979–84.
28. Zhang Z, Duvefelt K, Svensson F, et al. Two genes encoding
immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis. Genes Immun 2005;6:145–52.
29. Hugot JP, Chamaillard M, Zouali H, et al. Association of
NOD2 leucine-rich repeat variants with susceptibility to
Crohn’s disease. Nature 2001;411:599–603.
Am J Epidemiol 2006;164:615–623
623
30. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation
in NOD2 associated with susceptibility to Crohn’s disease.
Nature 2001;411:537–9.
31. Garland CF, Lillienfeld AM, Mendeloff AI, et al. Incidence
rates of ulcerative colitis and Crohn’s disease in fifteen areas of
the United States. Gastroenterology 1981;81:1115–24.
32. Sonnenberg A, McCarty DJ, Jacobsen SJ. Geographic variation of inflammatory bowel disease within the United States.
Gastroenterology 1991;100:143–9.
33. Shivananda S, Lennard-Jones J, Logan R, et al. Incidence of
inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).
Gut 1996;39:690–7.
34. Loftus EV, Schoenfeld P, Sandborn WJ. The epidemiology and
natural history of Crohn’s disease on population-based patient
cohorts from North America: a systematic review. Aliment
Pharmacol Therap 2002;16:51–60.
35. Ekbom A. The epidemiology of IBD: a lot of data but little
knowledge. How shall we proceed? Inflamm Bowel Dis
2004;10(suppl 1):S32–4.
36. Hugot JP, Alberti C, Berrebi D, et al. Crohn’s disease: the cold
chain hypothesis. Lancet 2003;362:2012–15.
37. Macintyre S, Ellaway A. Ecological approaches: rediscovering the role of the physical and social environment. In:
Berkman L, Kawchi I, eds. Social epidemiology. New York,
NY: Oxford University Press, 2000:332–48.
38. Rose G. The strategy of preventive medicine. New York, NY:
Oxford University Press, 1992.
39. Krieger N, Chen JT, Waterman PD, et al. Geocoding and
monitoring of U.S. socioeconomic inequalities in mortality
and cancer incidence: does the choice of area-based measure
and geographic level matter? The Public Health Disparities
Geocoding Project. Am J Epidemiol 2002;156:471–82.
40. Krieger N, Waterman PD, Chen JT, et al. Monitoring socioeconomic inequalities in sexually transmitted infections,
tuberculosis, and violence: geocoding and choice of areabased socioeconomic measures—The Public Health Disparities Geocoding Project (US). Public Health Rep
2003;118:240–60.
41. Mustard CA, Derksen S, Berthelot JM, et al. Assessing ecologic proxies for household income: a comparison of
household and neighborhood level income measures in the
study of population health status. Health Place 1999;5:
157–71.