RESEARCH ARTICLEAssociation between 25(OH)D Level,Ultrav.docx

RESEARCH ARTICLE
Association between 25(OH)D Level,
Ultraviolet Exposure, Geographical Location,
and Inflammatory Bowel Disease Activity: A
Systematic Review and Meta-Analysis
Chao Lu, Jun Yang, Weilai Yu, Dejian Li, Zun Xiang, Yiming
Lin, Chaohui Yu*
Department of Gastroenterology, the First Affiliated Hospital,
College of Medicine, Zhejiang University,
Hangzhou, 310003, China
* [email protected]
Abstract
Background
There is no consensus on the vitamin D levels and inflammatory
bowel disease (IBD).
Aim
To conduct a systematic review and meta-analysis to analyze
the relationship between IBD
and 25(OH)D, sun exposure, and latitude, and to determine
whether vitamin D deficiency
affects the severity of IBD.
Methods

We searched the PubMed, EBSCO, and ClinicalTrials.gov
databases to identify all studies
that assessed the association between 25(OH)D, sun exposure,
latitude, and IBD through
November 1, 2014, without language restrictions. Studies that
compared 25(OH)D levels
between IBD patients and controls were selected for inclusion
in the meta-analysis. We cal-
culated pooled standardized mean differences (SMDs) and odds
ratios (ORs).
Results
Thirteen case-control studies investigating CD and 25(OH)D
levels were included, and eight
studies part of above studies also investigated the relationship
between UC and 25(OH)D.
Both CD patients (SMD: 0.26 nmol/L, 95% confidence interval
[CI]: 0.09–0.42 nmol/L) and
UC patients (SMD: 0.5 nmol/L, 95% CI: 0.15–0.85 nmol/L) had
lower levels of 25(OH)D than
controls. In addition, CD patients and UC patients were 1.95
times (OR, 1.95; 95% CI, 1.48–
2.57) and 2.02 times (OR, 2.02; 95% CI, 1.13–3.60) more likely
to be 25(OH)D deficient than

controls. We also included 10 studies investigating the
relationship between CD activity and
vitamin D. Results showed that patients with active CD (CD
Activity Index�150) were more
likely to have low vitamin D levels. In addition, whether low
sun exposure and high latitude
were related to a high morbidity of CD need to be provided
more evidence.
PLOS ONE | DOI:10.1371/journal.pone.0132036 July 14, 2015
1 / 16
OPEN ACCESS
Citation: Lu C, Yang J, Yu W, Li D, Xiang Z, Lin Y, et
al. (2015) Association between 25(OH)D Level,
Ultraviolet Exposure, Geographical Location, and
Inflammatory Bowel Disease Activity: A Systematic
Review and Meta-Analysis. PLoS ONE 10(7):
e0132036. doi:10.1371/journal.pone.0132036
Editor: John Green, University Hospital Llandough,
UNITED KINGDOM
Received: March 25, 2015
Accepted: June 9, 2015
Published: July 14, 2015
Copyright: © 2015 Lu et al. This is an open access
article distributed under the terms of the Creative
Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any

medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper.
Funding: The authors have no support or funding to
report.
Competing Interests: The authors have declared
that no competing interests exist.
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Conclusion
Our study shows that IBD patients have lower vitamin D levels.
For active CD patients, vita-
min D levels were low. These findings suggest that vitamin D
may play an important role in
the development of IBD, although a direct association could not
be determined in our study.
Introduction
Inflammatory bowel disease (IBD) including Crohn's disease
(CD) and ulcerative colitis (UC),
refers to a group of chronic gastrointestinal disorders
characterized by dysregulated intestinal
inflammation[1]. IBD can be caused by environmental
factors[2], a genetic susceptibility such as

NOD2 mutation[3] or interleukin (IL)-23 receptor mutation[4],
immune dysregulation[5], or
other factors. As a public health problem, IBD has a high
incidence in developed and northern
countries, and although still low, the incidence of IBD in
developing areas is increasing[2, 6].
Some studies have suggested that vitamin D as a
immunoregulatory element plays an
important role in the occurrence and progression of IBD[7, 8].
Vitamin D is an indispensable
element in the human body that is found in two main forms:
storage-type 25(OH)D, which is
hydroxylated by the liver, and active-type 1,25(OH)2D, which
is hydroxylated by the kidney. It
is also known as a “sunshine element”, because it can be
synthesized upon exposure to ultravio-
let (UV) rays. The biological effects of vitamin D are primarily
mediated by the vitamin D
nuclear receptor (VDR)[9], and it is widely known to act in the
metabolism of bone. However,
the discovery of VDR expression in more target tissues, such as
the kidney, thyroid, intestine,
skin, immune cells, nonparenchymal hepatocytes, and biliary
epithelial cells[10, 11], suggests
that vitamin D may influence systemic human metabolism
including the immune system.
Mouli et al identified an association between vitamin D
deficiency and the development of IBD
and also found that vitamin D deficiency influences disease
severity[12]. The immunomodula-
tory function of vitamin D and immune factors in the
pathogenesis of IBD suggest that vitamin
D levels are commonly low among patients of IBD. In addition,
people living in areas at high
latitude that receive little sun expose synthesize low levels of

vitamin D and have higher inci-
dence. Such observations provide supporting evidence for the
relationship between vitamin D
and IBD.
In this study, we conducted a meta-analysis and systematic
review to analyze the relation-
ships between IBD and vitamin D, sun exposure, and latitude.
We also aimed to determine
whether vitamin D deficiency directly affects the severity of
IBD.
Methods
Data sources and study selection
We searched articles published from January 1, 2000 to
November 1, 2014 in PubMed, Clini-
calTrials.gov, and EBSCO databases without language
restrictions. Following terms: inflamma-
tory bowel disease, IBD, Crohn's disease, CD, ulcerative colitis,
UC, vitamin D, 25(OH) vitamin
D, 25(OH)D were used. “OR” was used as the set operator to
combine different sets of results.
We selected studies that reported data on vitamin D levels, sun
exposure, latitude, and IBD
with or without mention of disease severity. Controlled clinical
trials investigating vitamin D
levels and IBD were included in order to conduct a meta-
analysis so that we can conclude
whether vitamin D is related to IBD. Then, a systematic review
was conducted instead of meta-
analysis regarding the relationship between vitamin D and IBD
activity due to the small
The Relationship between IBD and 25(OH)D Level

2 / 16
number of high quality papers and lacking of data. In addition,
we examined correlations
between vitamin D and latitude or annual sunshine exposure in
the cities where the included
studies were performed in order to assess whether living in
areas at high latitude or with low
sunshine exposure was related to IBD. Age, sex, and other
confounding factors were also con-
sidered. We excluded papers that did not provide original data,
animal studies, in vitro studies,
and studies focused on conditions affected by vitamin D
metabolism.
Data abstraction
We abstracted main study characteristics, including
patient/volunteer characteristics (includ-
ing sex, age, and number of people), research country,
publication year, serum vitamin D levels
as continuous variable, and the cut-off level used to define
vitamin D deficiency as dichoto-
mous variable. We obtained data for latitude and annual
sunshine exposure according to the
cities where the included studies were conducted. Data for
annual sunshine exposure were
obtained from the Web of the Hong Kong Observatory
(http://gb.weather.gov.hk/contentc.
htm). All data were double checked by one author. Two
investigators independently examined
and selected papers for inclusion in our analyses. Another two
investigators assessed the quality
of papers by applying the Strengthening the Reporting of

Observational studies in Epidemiol-
ogy (STROBE) checklist[13] or other tools[14, 15].
Statistical analysis
We combined the standardized mean difference (SMD) for
studies that reported mean and
standard deviation (SD) values for vitamin D levels of IBD
patients and controls. 25(OH)D
was the main form of vitamin D considered in the included
studies. The cut-off level for 25
(OH)D deficiency was defined as less than 50 nmol/L[16]. For
two studies[17, 18] that pro-
vided 95% confidence intervals (CIs) instead of SDs, we
obtained a final SD using a reduction
formula[19]. Because of the different characteristics between
CD and UC, we analyzed them
independently. To correct for bias in a small sample size, we
used a random effects model. In
our study, three studies involving pediatric participants were
included[18, 20, 21]. Considering
the possible differences in vitamin D levels between children
and adults, we also opted to strat-
ify our analyses in pediatric and adult participants. For studies
that reported vitamin D defi-
ciency as a dichotomous variable, we pooled the ORs using the
Mantel-Haenszel method with
a fixed effects model. In addition, the linear regression analysis
was used to correlate vitamin D
and latitude, annual sunshine exposure. Statistical heterogeneity
was assessed by Cochran’s Q-
test and the I2 statistic. We assessed publication bias with
Egger’s test. All analyses were carried
out through the application of the commands metan and
metabias in STATA 12. Linear regres-
sion analysis was operated in SPSS 17.0 (IBM, Chicago, IL,
USA).

Results
Basic characteristics
Our search identified 1756 related references, of which 21
papers met our inclusion criteria
(Fig 1). The reasons for exclusion were shown in Fig 1. The 21
studies included 5 studies con-
ducted in Europe, 9 in North America, 4 in Asia, 1 in Brazil,
and 2 in Australia. Our study
included 13 studies investigating the association between CD
and vitamin D levels [17, 18, 20–
30]. Of them, eight studies also referred to the relationship
between UC and vitamin D levels
[17, 20, 21, 23, 24, 27, 29, 30]. Patients’ basic characteristics
are presented in Table 1. However,
disease durations, years of follow-up since diagnosis, and
surgical treatment were not included
due to the lack of data. The participants in three studies[18, 20,
21] were children, and those in
3 / 16
http://gb.weather.gov.hk/contentc.htm
http://gb.weather.gov.hk/contentc.htm
the other studies were adults. In addition, eight studies were
used to analyze dichotomous
exposure (vitamin D deficiency) in CD[21–24, 26, 28, 31, 32],
of which three studies also
referred to UC[21, 23, 24]. Continuous variable can directly
reflect the relationship between

IBD and vitamin D levels, whereas dichotomous variables
indicate morbidity of IBD under dif-
ferent vitamin D classifications. The combination of continuous
and dichotomous variables
can reflect the relationship between IBD and vitamin D better.
Among 21 studies included, we
Fig 1. Flow diagram of searching.
doi:10.1371/journal.pone.0132036.g001
4 / 16
also analyzed 10 studies to investigate the relation of vitamin D
and IBD activity[23, 25, 29, 30,
33–38].
Association of IBD with vitamin D
We conducted a meta-analysis of vitamin D levels and CD based
on data for 796 CD patients
and 761 controls. The average 25(OH)D level in CD patients
was 0.26 nmol/L less than that in
controls (SMD = 0.26 nmol/L, 95% CI = 0.09–0.42 nmol/L, I2 =
54.1%, P = 0.01; Fig 2). When
we excluded children (131/796 CD patients, 212/761 controls),
we found that the average 25
(OH)D level in adult CD patients (665/796) was 0.25 nmol/L
lower than that in controls (549/
761) (SMD = 0.25 nmol/L, 95% CI = 0.06–0.44 nmol/L, I2 =
54.9%, P = 0.018). In contrast, no
statistically significant difference was found between the

25(OH)D levels of pediatric CD
patients and controls.
Table 1. Studies on vitamin D levels in CD patients, UC
patients, and controls.
Author year
(ref)
CD(n)/ UC
(n)/
Control(n)
Assay method for
vitamin D
Age (CD/UC/
Control)
Gender
(male/female)
(CD;UC;
Control)
25(OH)D in
CD(nmol/L)
(mean±SD)
*
25(OH)D in
UC (nmol/L)
(mean±SD)
*
25(OH)D in
Controls

(nmol/L)
(mean±SD)*
P#
Joseph 2009
[26]
34/0/34 Radioimmunoassay 39.2 ± 12.9/-/ 38.9
±13.4
24/10;-; 24/10 40.6±27 - 56.9±29.7 <0.05
Jørgensen
2013 [25]
182/0/62 Chromatography 36 (17–78)/-/32
(18–62) **
78/104;-; 30/
32
69±33 - 65±25 NS***
Garg 2013
[17]
40/31/23 Electrochemilumine-
scence assay
41 (23–76)/41
(23–76)/39 (22–
68) **
22/18;17/
14;10/13

70±36.3 70±32.7 66±43.5 NS/NS
El-Matary
2011 [20]
39/21/56 Competitive protein
binding assay
12.2±3.2/12.4±37/
11.3±4.2
19/20;10/
11;25/31
66.7±27.3 56.9±22 81.7±15.4 <0.05/
<0.05
Grunbaum
2013 [24]
34/21/48 Radioimmunoassay 39.9 ± 12.3/
44.2 ± 13.7/
39.6 ± 13.8
13/21;8/13;10/
38
71.1±31.1 71.4±36.3 68.3±26.2 NS/NS
Tajika 2004
[29]
binding assay

37.6±7.5/47.6
±12.4/37.7±10.0
25/8;6/5;8/7 37.9±16.2 43.9±11.7 42.2±13 <0.05/
<0.05
Dumitrescu
2014 [23]
14/33/94 Chromatography 36 ± 9/42 ± 14/
42 ± 12
8/6;17/16;50/
44
57.4±25 59.9±27.5 77.4±32.4 <0.05/
<0.05
Veit 2014 [21] 40/18/116 Chemiluminescent
immunoassay
16.61±2.20/16.13
±1.99/14.56±4.35
24/16;7/11;49/
67
61.7±24.4 53.3±25.5 65.3±28 NS/NS
de Bruyn
2014 [22]
101/0/41 Chemiluminescent
immunoassay
41 (30–50)/-/28

(24–39) **
31/70;-;8/33 51.6±26.6 - 60.8±27.6 NS
Suibhne 2012
[28]
81/0/70 Radioimmunoassay 36.43±11.00/-/
36.34±9.53
32/49;-;28/42 47.6±27.2 - 51.9±24.5 NS
Middleton
2013 [18]
binding assay
17.0(15.0–18.5)/-/
11.0(5.0–15.0)**
32/20;-;15/25 40.2±15.7 - 40.7±16.2 NS
Souza 2008
[27]
39/37/40 - 32.1±8.7/35.0
±8.5/34.0±7.0
21/18;12/
25;16/24
64.6±20.5 54.4±20 85.9±31.9 <0.05/
<0.05
Tan 2014 [30] 107/124/

122
ELISA 38.0 ± 15.3/
39.6 ± 14.4/
39.43 ± 12.71
68/39;63/
61;67/55
28.9±12.5 25.8±11.1 32.1±11 <0.05/
<0.05
*Vitamin D levels reported as nmol/L. Vitamin D levels
measured in ng/mL were converted to nmol/L by multiplying by
2.496.
** Median and range
***NS, not significant
#P compares CD patients or UC patients to controls.
doi:10.1371/journal.pone.0132036.t001
5 / 16
For the meta-analysis of vitamin D levels and UC, 296 UC
patients and 514 controls were
included. On average, the average 25(OH)D level in UC patients
was 0.5 nmol/L lower than
that in controls (SMD = 0.5 nmol/L, 95% CI = 0.15–0.85
nmol/L, I2 = 77.5%, P<0.01; Fig 3).

However, neither adult UC patients (218/257) nor pediatric UC
patients (39/257) had signifi-
cantly different levels from controls independently. Different
methods for quantifying vitamin
D levels did not show changes in the inferences.
In addition, eight reports described dichotomous variables for
vitamin D deficiency in
patients with CD [21–24, 26, 28, 31, 32]. Three studies
investigated UC and vitamin D defi-
ciency [21, 23, 24](Table 2). CD patients were 1.95 times (OR =
1.95, 95% CI = 1.48–2.57, I2 =
0, P = 0.866) more likely to suffer vitamin D deficiency than
controls (Fig 4). And no publica-
tion bias was found under Egger’s test (P = 0.383, Fig 5).
Similarly, UC patients were 2.02 times
more likely to experience vitamin D deficiency than controls
(OR = 2.02, 95% CI = 1.13–3.60,
I2 = 0, P = 0.773; Fig 6).
Association of IBD activity with vitamin D
Our results supported the conclusion that CD and UC patients
have lower vitamin D levels
than control individuals. Based on this phenomenon, we
hypothesized that vitamin D levels
are lower in patients with active IBD. To investigate this
hypothesis, we collected only articles
regarding CD, because the number of studies in UC patients was
too few. First, we assessed dis-
ease activity according to the Crohn’s Disease Activity Index
(CDAI) as described by Best et al
[39] or the Harvey-Bradshaw index (HBI) presented by Harvey
et al [40]. A CDAI <150 or
Fig 2. Meta-analysis of studies reporting 25(OH)D levels in CD
patients vs. controls, a standardized

mean difference with a 95% confidence interval and weight
percentage. Subtotals of adults and children,
and overall population.
6 / 16
HBI score <5 was defined as CD remission, whereas a CDAI
�150 or HBI score �5 was
defined as activity. The Pediatric Crohn’s Disease Activity
Index (PCDAI) was applied in pedi-
atric cases of CD. Ten studies conformed to the requirements
and were divided into a continu-
ous variable group [23, 25, 30, 34, 35] (Table 3) and a
dichotomous variable group [29, 33, 36–
38] (Table 4). Due to the lack of data, a meta-analysis was not
possible. In the continuous vari-
able group, four studies supported our hypothesis that CD
patients with a CDAI<150 or
HBI<5 had higher vitamin D levels compared to those in
patients with active CD. The remain-
ing study [35] reported that vitamin D levels with CDAI<150
was higher, but not significantly
(P = 0.389), which didn’t statistically support our hypothesis,
possibly because their study pop-
ulation was relatively small. In the dichotomous variable group,
only one study [38] indicated
that CD patients with vitamin D deficiency had a higher activity
score than controls
(P = 0.002). The other four studies found no statistical

difference about active score between
vitamin D deficiency and sufficiency (Table 4). This may have
been affected by differences in
the cut-off value for vitamin D deficiency or the bias of
subjects. More data and studies are
needed to draw an exact conclusion, but currently, we
determined that CD patients in remis-
sion were more likely to have higher vitamin D levels than
those with active disease.
Latitude, annual sunshine exposure, vitamin D and IBD
Economou et al [41] confirmed that the incidence of IBD is
higher in countries with low sun
exposure and located at a high latitude. We also tried these
findings. It is well known that vita-
min D synthesis depends on exposure to sunlight and solar
ultraviolet radiation, which is
affected by latitude, season, and duration of daily sunshine[42].
We correlated vitamin D levels
with the latitude and annual sunshine exposure of the cities
where the included studies were
Fig 3. Meta-analysis of studies reporting 25(OH)D levels in UC
patients vs. controls, a standardized
mean difference with a 95% confidence interval and weight
percentage. Subtotals of adults and children,
and overall population.
7 / 16

conducted. Due to a lack of adequate data, we found no
correlation between vitamin D and lati-
tude or vitamin D and annual sunshine exposure in CD (r =
0.069, P = 0.856; r = -0.439,
P = 0.265, respectively) or in control (r = -0.355, P = 0.344; r =
-0.745, P = 0.059, respectively).
In addition, three studies [43–45] studying the link between
sunshine and IBD showed that
low sun exposure was highly associated with CD, but not UC.
Limketkai et al also indicated
that lower sunshine exposure is associated with greater rates of
hospitalization, prolonged hos-
pitalization, and the need for bowel surgery [44]. With respect
to latitude and IBD, two large-
scale perspective studies from the USA [46] and Europe [47]
reported an association between
latitude and IBD. As a result of the limitations of included
articles, we cannot directly prove
that lower sun exposure and higher latitude lead to a higher
incidence of IBD. Generally, more
studies investigating correlations between vitamin D levels and
IBD are needed and then we
can merge the data to obtain more reliable results regarding
correlations between vitamin D
levels and latitude or annual sunshine exposure in future
analyses.
Discussion
From this systematic review and meta-analysis, we concluded
that vitamin D levels are strongly
associated with IBD. We found lower vitamin D levels in CD
and UC patients. Moreover, CD
and UC patients were 1.95 times and 2.02 times, respectively,
more likely to be vitamin D defi-
cient. We also found that vitamin D levels influence the activity

of CD.
In our analysis of vitamin D related to latitude and annual
sunshine exposure, we expected a
negative correlation between vitamin D and latitude, but a
positive correlation between vitamin
Table 2. Data for vitamin D deficiency among CD patients, UC
patients, and controls.
Author/year
(ref)
CD(n)/
UC(n)/
Control
(n)
Age (CD/UC/
Control)
Gender
(male/
female)
(CD;UC;
Control)
CD
Deficiency
(n)
CD
Sufficiency
(n)
UC

Deficiency
(n)
UC
Sufficiency
(n)
Control
Deficiency
(n)
Control
Sufficiency
(n)
P*
Joseph 2009
[26]
34/0/34 39.2 ± 12.9/-/
38.9±13.4
24/10;-
;24/10
27 7 - - 17 17 <0.05
Prosnitz
2013 [32]
78/0/
221
12.7±2.8/-/
13.5±4.4

44/34;-
;112/109
33 45 - - 57 164 <0.05
de Bruyn
2014 [22]
101/0/
41
41 (30–50)/-/
28 (24–39) **
31/70;-;8/
33
55 46 - - 18 23 NS#
Suibhne
2012 [28]
81/0/70 36.43
±11.00/-/
36.34±9.53
32/49;-
;28/42
51 30 - - 36 34 NS
McCarthy
2005 [31]
44/0/44 36.7±11.0/-/

36.9±11.1
15/29;-
;15/29
15 29 - - 7 37 NS
Grunbaum
2013[24] ***
34/21/
48
39.9±12.3/
44.2±13.7/
39.6±13.8
13/21;8/
13;10/38
10 21 7 12 11 34 NS/
NS
Dumitrescu
2014 [23]
14/33/
94
36±9/42±14/
42±12
8/6;17/
16;50/44
5 9 10 23 19 75 NS/

NS
Veit 2014
[21]
40/18/
116
16.61±2.20/
16.13±1.99/
14.56±4.35
24/16;7/
11;49/67
16 24 9 9 31 85 NS/
<0.05
* P compares CD or UC patients to controls.
** Median and range
***Because of some missing data on serum 25[OH] vitamin D
levels, the number of deficiency and sufficiency together didn't
match the total number.
#NS, not significant
8 / 16

D and annual sunshine exposure. The relationship with latitude
was roughly as expected (the
correction in IBD was very low with a positive correlation
factor of 0.069), whereas that with
sunshine exposure was opposite to our expectation.
Confounding factors, such as Human
Development Index, working environment (malnutrition low-
income populations are more
Fig 4. Meta-analysis of studies reporting dichotomous outcomes
of 25(OH)D levels in CD patients vs.
controls and estimated OR with a 95% confidence interval and
weight percentage.
Fig 5. Egger’s test results for publication bias about
dichotomous outcomes of 25(OH)D levels in CD.
9 / 16
inclined to work outdoor), the vitamin D content of food, and
the frequency of outdoor exer-
cise that we could not analyze may have influenced the results.
In addition, based on our data,
we observed that the trend between vitamin D levels with
respect to latitude and sunshine
exposure was more obvious in control patients, which is
consistent the hypothesis that there

may be a relationship between vitamin D levels and IBD
activity due to lower vitamin D levels
in IBD patients.
Fig 6. Meta-analysis of studies reporting dichotomous outcomes
of 25(OH)D levels in UC patients vs.
controls and estimated OR with a 95% confidence interval and
weight percentage.
Table 3. Data for continuous variable group on vitamin D and
CD activity.
Author year
(ref)
N(active/
inactive)
Age Vitamin D levels
(active/inactive)(nmol/
L)
Country Type of CD
activity
Results
Jørgensen
2013 [25]
- - -/64* Denmark CDAI** Vitamin D level with CDAI<150
was higher than
that for mild or moderate CD activity (P<0.01)

Hassan 2013
[35]
14/12 34 ± 18 23.2 ± 18.5/29.5 ± 2.0 Iran CDAI Vitamin D level
with CDAI<150 was higher, but
not significantly (P = 0.389)
Dumitrescu
2014 [23]
- 36 ± 9 -/64.9 ±17.5 Romania CDAI CD patients with a
CDAI�150 had significantly
lower vitamin D levels than those with a
CDAI<150 (P<0.05)
Ham 2014 [34] 20/17 - 67.4 ± 5.0/94.8 ± 7.5 USA HBI***
Vitamin D level in patients with active disease
was lower than that in patients in remission
(P = 0.02)
Tan 2014 [30] - - -/32.8 ± 13.6 China HBI Patients with active
disease had significantly
lower levels of vitamin D than those in remission
(P<0.05)
* We could not combine data to calculate vitamin D levels of
active
**CDAI: Crohn’s Disease Activity Index
***HBI: Harvey-Bradshaw index

10 / 16
Yang et al indicated that maximal vitamin D supplementation
with 5,000 IU/d can signifi-
cantly increased serum vitamin D levels from 16±10 ng/ml to
45±19 ng/ml (P<0.0001) and
reduce the unadjusted mean CDAI scores by 112±81 points from
230±74 to 118±66 (P<0.0001)
[48]. In addition, in Bendix-Struve’s study, patients treated with
high dose vitamin D (1200 IU/
d) showed CDAI scores reduced from 37 (range 8–111) to 34
(range 23–53). Meanwhile, CDAI
scores in the control group (placebo treated) increased from 23
(range 0–187) to 45 (range
0–273)[49]. These results suggest that vitamin D
supplementation can alleviate the severity of
IBD and further provide evidence for the role of vitamin D in
the development of IBD.
As an intestinal disease, the influence of gastrointestinal
inflammation in the pathogenesis
of IBD could not be ignored. Papadakis et al confirmed that CD
and UC are related to specific
cytokine profiles: interferon (IFN)-γ, tumor necrosis factor
(TNF)-α, and interleukin (IL)-12
levels are elevated in CD, whereas IL-5 is increased in UC[50].
These specific pro-inflammatory
cytokines were found in the inflamed mucosa of CD and UC
patients. Meanwhile, vitamin D
plays an important role in the immune system[51]. It can
mediate T helper type 1 (Th1) cells,
which can produce pro-inflammatory cytokines including IFN-γ,
IL-2, and TNF-α [52, 53].

Muller et al indicated that vitamin D can inhibit the release of
TNF-α [54], and VDR-/- mice
showed more production of TNF-α, IL-6, and IL-1β[55],
illustrating the important role of
VDR in IBD. Obviously, the immunologic and inflammatory
relationships between IBD and
vitamin D were responsible for the results of our study. In
addition to immune factors, vitamin
D signaling can regulate the expression of NOD2 [56] and
autophagy homeostasis including
TNF-α–induced autophagy[57], which may also play an
important role in IBD.
Additional experimental evidence from animal studies further
supports the immunologic
role of vitamin D and VDR in IBD. VDR-/- mice treated with
dextran sodium sulfate (DSS)
showed elevated levels of IFN-γ and TNF-α and had
significantly fewer intact crypts, more
intestinal injury, and more inflammation[58]. In addition, VDR-
/- mice had an increased bac-
terial burden and mortality, more easily detectable levels of IL-
6 and elevated NF-κB activity in
intestinal epithelia after Salmonella infection[59]. For IL-10-/-
mice models, double knockout
mice (double IL-10/VDR knockout) developed more severe IBD
than single VDR-/- and IL-
10-/- mice[60].
Table 4. Data for dichotomous variable group on vitamin D
deficiency and CD activity.
Author year
(ref)
Cut-off of vitamin D

deficiency (nmol/L)
N(VD deficiency/
without
deficiency)
Active score(VD
deficiency/without
deficiency)
Country Type of CD
activity
Results
Tajika 2004
[29]
25 9/24 111.8±46.7/ 73.8±39.3 Japan CDAI* CDAI was higher
in patients with
vitamin D deficiency, but not
significantly(P>0.05)
Levin 2011
[36]
50 - 10.5±6.9/ 13.1±11.2 Australia PCDAI** No differences
between the two
groups
Ulitsky 2011
[38]
50 241/263 3.55/2.61 USA HBI*** HBI in patients with vitamin
D
deficiency was higher (3.55 vs.

2.61, P = 0.002)
Sentongo
2002 [37]
38 18/94 17.08±11.17/ 11.63
±12.52
USA PCDAI No differences between the two
groups
Fu 2012 [33] 50 17/23 - Canada HBI No differences between
the two
groups
*CDAI: Crohn’s Disease Activity Index
**PCDAI: Pediatric Crohn’s Disease Activity Index
***HBI: Harvey-Bradshaw index
11 / 16
In addition, in colitis mice models treated with trinitrobenzene
sulfonic acid (TNBS), treat-
ment with the vitamin D analogue calcitriol could down-
regulate the pro-inflammatory
response[61]. These animal studies proved the importance of
vitamin D and VDR in inflam-

mation of the gut and in the pathogenesis of IBD.
Nevertheless, IBD also leads to some clinical symptoms, such
as impaired absorption of
nutrients, abdominal pain, and dysbacteriosis including
clostridium difficile infection[62],
which can influence the absorption of vitamin D. Although
many of the studies described
above stated that vitamin D levels influence the development of
IBD, we still cannot ignore
that vitamin D levels are likely affected by IBD. More
prospective studies are needed to better
understand causation between vitamin D levels and IBD.
We have summarized the relationship between IBD and vitamin
D levels, ultraviolet expo-
sure, and geographical distribution. However, some other
factors may also influence the mor-
bidity of IBD. Seasonal variation is one factor that we did not
analyze. Kini et al reported that
serum 25(OH)D levels were lower in winter than in summer
(35.9±17.5 vs. 69.6±19.0 nmol/L,
P<0.0005) [63], but found no significant difference in the mean
CDAI score between the sea-
sons (103.9±76.9 vs. 90.2±84.0, P = 0.365). Aratari et al noted
that the onset of CD symptoms
occurred more frequently during spring and summer[64].
However, a Japanese study showed
that the onset of symptoms in UC patients frequently occurred
during the winter[65]. In addi-
tion, smoking has also been proven to be associated with
IBD[28]. Ethnicity factors were exam-
ined as well. Although vitamin D levels were significantly
higher in Caucasians than in non-
Caucasians (Asian and Black individuals), no significant
association was found between the

morbidity and severity of IBD and ethnicity[33]. VDR plays a
key role in IBD, and genetic vari-
ants of VDR have been shown to be associated with an
increased risk of IBD. A meta-analysis
showed a significant increase in CD risk for Europeans carrying
the TaqI tt genotype and a sig-
nificant decrease in CD risk for all carriers of the Apal "a"
allele[66]. In Asians, the ff genotype
of FokI was associated with an increased UC risk[66]. These
results indicate that other environ-
mental factors and genetic variation also will affect vitamin D
levels and determine the devel-
opment of IBD.
To our knowledge, this is the first meta-analysis and systemic
review to investigate the asso-
ciation of vitamin D levels with IBD as well as the activity of
IBD. We reviewed many reports
in order to add strength to our study. However, several
limitations of our study still exist. First,
in most included studies, the diagnostic criteria for IBD were
not mentioned, which could
directly cause selection bias in the included participants.
Pathological diagnosis is considered
the gold standard. However, in some studies, IBD was
diagnosed under colonoscopy directly,
by fecal lactoferrin, by cellular immunology, or another method,
and this inconsistency greatly
increases the false positive rate and influences the results of
included studies. Therefore, in the
future, the diagnostic criteria need to be unified. Second, the
cut-off level for defining vitamin
D deficiency varied among the included studies. The Institute of
Medicine recommended 50
nmol/L as the cut-off level[67], and different division standards
will directly cause heterogene-

ity among the results. Third, numerous original studies did not
adjust for potentially relevant
confounders, such as smoking, latitude, life style, gene
polymorphisms, and so on. Any of these
factors could lead to bias in the results. In addition, the
statistical heterogeneity that appeared
in our analysis would also have a small effect on the reliability
of our results.
Conclusions
We have demonstrated that vitamin D levels are lower in IBD
patients, suggesting that vitamin
D plays an important role in the pathogenesis of IBD. However,
we still do not know which
specific mechanism plays the main role in this relationship.
Potential mechanisms included
12 / 16
immune-mediated mechanisms, the anti-inflammatory action of
vitamin D, and gene regula-
tion related to vitamin D levels.
Supporting Information
S1 File. PRISMA 2009 Checklist.
(DOC)
Author Contributions
Conceived and designed the experiments: CHY CL. Performed
the experiments: CL JY WLY.
Analyzed the data: CL DJL. Contributed

reagents/materials/analysis tools: CL ZX. Wrote the
paper: CL. Assessed quality of the papers: CL YML.
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16 / 16
http://dx.doi.org/10.1017/s0029665111001650
http://dx.doi.org/10.1038/nri2378
http://dx.doi.org/10.4049/jimmunol.1203273
http://dx.doi.org/10.4049/jimmunol.1203273
http://dx.doi.org/10.1074/jbc.C109.071225
http://dx.doi.org/10.1186/1471-2172-8-5
http://dx.doi.org/10.1186/1471-2172-8-5
http://dx.doi.org/10.2353/ajpath.2010.090998
http://dx.doi.org/10.1111/j.1365-2567.2005.02290.x
http://dx.doi.org/10.1111/j.1365-2567.2005.02290.x
http://dx.doi.org/10.1124/jpet.107.127209

http://dx.doi.org/10.1016/j.dld.2005.10.002
http://dx.doi.org/10.3748/wjg.v19.i47.9063
http://dx.doi.org/10.1210/jc.2011-2218
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Engineering Analysis Final Exam
1 Problem 1
Explain what a basis for a vector space is.
2 Problem 2
Find the eigenvectors and eigenvalues of the following matrix.
Write the matrix of eigenvectors and state its rank. If
possible, invert it and show that
P−1AP = Λ
. [

5 3
−2 1
]
3 Problem 3
P−1AP = Λ
. [
7 1
−4 3
]
4 Problem 4
P−1AP = Λ
1 −3 3
3 −5 3
6 −6 4

5 Problem 5
Use Gram-Schmidt process to compute an orthogonal basis for
the following set of vectors. Use the first vector as a
starting point for the orthonormal basis that you find:[
1 1 1 1
][
1 2 4 5
][
1 −3 −4 2
]
(1)
1
6 Problem 6
P−1AP = Λ
−1 4 2
−3 4 0

−3 1 3
7 Problem 7
Use Gram-Schmidt process to compute an orthogonal basis for
the following set of vectors. Use the first vector as a
starting point for the orthonormal basis that you find:[
1 −1 1
][
1 0 1
][
1 1 2
]
(2)
8 Problem 8
P−1AP = Λ
−1 −1 1
0 −2 1

0 0 −1
2
People, Place, and Region: 100 Years of Human
Geography in the Annals
Audrey Kobayashi
Department of Geography, Queen’s University
Human geography articles published in the Annals of the
Association of American Geographers over the past century
have gone through several overlapping phases that include
Darwinian environmentalist approaches during the
early part of the century, a strongly antideterminist cultural
geography influenced by Carl Sauer at midcentury, and
a science of “space” supported by quantitative methods in the
postwar period. All three approaches take a regional
perspective, although with very different definitions of the
region. During the 1970s, regional and quantitative
methods remained strong, although humanism and Marxism
became the two dominant methodologies. Since
the 1980s, and the emergence of a variety of poststructuralist
perspectives, these two approaches no longer run
on separate tracks. The past two decades have seen the rather
later influence of feminism and antiracism as major
themes in the Annals, as well as strengthening of economic and
political theories. Presidential addresses have
played an important role in influencing, or responding to, new

directions in geography. Key Words: Annals of
the Association of American Geographers, human geography,
methodology, place, region.
Los artı́culos de geografı́a humana publicados en Annals of the
Association of American Geographers durante el
pasado siglo han pasado por varias fases traslapadas que
incluyen los enfoques ambientalistas darwinianos en
los albores del siglo, una geografı́a cultural fuertemente
antideterminista influida por Carl Sauer a mediados del
siglo, y una ciencia del “espacio” apoyada en métodos
cuantitativos en el perı́odo de la posguerra. Todos los tres
enfoques adoptaron una perspectiva regional, aunque a partir de
muy diferentes definiciones del término región.
Durante los años 1970, los métodos regional y cuantitativo
permanecieron fuertes, aunque el humanismo y el
marxismo se convirtieron en las dos metodologı́as dominantes.
Desde los años 1980 y con la emergencia de una
variedad de perspectivas posestructuralistas, esos dos enfoques
ya no marchan en pistas separadas. Las pasadas dos
últimas décadas han presenciado la muy tardı́a influencia del
feminismo y el antirracismo como temas principales
de Annals, lo mismo que un fortalecimiento de las teorı́as
económicas y polı́ticas. Los discursos presidenciales
de la AAG han jugado un papel importante en términos de
influencia o respuesta sobre los nuevos rumbos de
la geografı́a. Palabras clave: Annals of the Association of
American Geographers, geograf ́ıa humana, metodologı́a,
lugar, región.
When the three concepts of “people, place,and region” were
chosen in 1999 to encom-pass a broad swath of what is widely
referred
to as human geography, it was with considerable and
thoughtful, albeit at times contentious, debate. The
ontological status of these concepts or, more correctly,

geographers’ interpretations of these concepts, deserves
a fuller discussion than has yet occurred either in the
Annals or the wider human geography literature. I use
these few pages to look back on a century of human
geography in the Annals, with the clear caveat that this
account is limited to articles published in the Annals
and makes no attempt to address the wider geographi-
cal literature. I have attempted to convey the words and
ideas of those geographers who have most influenced
our discipline through their writing in the Annals.
Neutrality is difficult in a discipline where through
the years there have been many normative opinions as
to what we can, should, and should not study. Pres-
idential addresses, many of them cited here, contain
some of the most inspiring ideas and some of the most
petty admonishments, ranging from environmentalism,
Annals of the Association of American Geographers, 100(5)
2010, pp. 1095–1106 C© 2010 by Association of American
Geographers
Published by Taylor & Francis, LLC.
1096 Kobayashi
to region, to spatial systems, to human interactions
with one another, a circuitous progression marked with
plenty of debate of the how and the why. Given the task
at hand, I try to convey these debates in a descriptive,
nonjudgmental manner, but I apologize in advance if
by omission, complicity, or implication, my own views
occasionally seep through.

Human geography, whether by design or lack of
interest, was not very important in the Association of
American Geographers (AAG) and its publications for
at least the first two decades. I suspect that there might
have been some design on the part of the first editor,
Richard Elwood Dodge, because the publications of
titles and abstracts of the annual meetings (published
in the Annals from the first meeting in 1904 [1911]
until the sixty-third meeting in 1967) contain a signifi-
cant amount of human geography, whereas articles pub-
lished during the first decade that might count as human
geography number only six1: “The Barrier Boundary of
the Mediterranean Basin and its Northern Breaches as
Factors in History” (Semple 1915); “The Oasis of Tuba,
Arizona,” (Gregory 1915); “Some Considerations on
the Geographical Provinces of the United States”
(Jefferson 1917); “Sriharikota and the Yanadis”
(Cushing 1917); “The Boundaries of the New England
States,” (Cushing 1920); and “Genetic Geography: The
Development of the Geographic Sense and Concept”
(Dryer 1920). All six are preoccupied with defining
regions, include people among a range of objects found
within regions, and are strongly Darwinian in approach.
Gregory, Cushing, and Dryer all refer in some way to
the “savage,” uncivilized character of the humans they
describe. Epistemologically, all six share with other
geographers of the time—who were more interested in
physiographic features of regions—a view of geography
as a unified science based on Kantian epistemology.2 In
his presidential address of 1922, Harland Barrows val-
idated this synoptic approach, although with a gentle
admonition as to the dangers of overly deterministic
determinism:
Geography will aim to make clear the relationships be-
tween natural environments and the distribution and ac-

tivities of man. Geographers will, I think, be wise to view
this problem in general from the standpoint of man’s ad-
justment to environment, rather than from that of envi-
ronmental influence. The former approach is more likely
to result in the recognition and proper valuation of all the
factors involved, and especially to minimize the danger
of assigning to the environmental factors a determinative
influence which they do not exert. (Barrows 1923, 2)
A big upset occurred a year later. In the same volume
in which Huntington (1924) published an unabashed
statement of his thesis on determinism and natural se-
lection, Carl Sauer (1924) challenged the discipline to
cease and desist. The “bias of determinism” (18), he
claimed, was unscientific, biased, dogmatic, unsystem-
atic, and undisciplined. A year later, J. K. Wright went
further:
Danger besets the man who would study the relation be-
tween geographical environment and human thought. So
complex are the factors which mold our mental processes,
so imperfect our understanding of the relation between
geography and the physical—let alone intellectual—
activities of humanity; and so great the risk of unfounded
generalization, that critical geographers have fought shy
of the subject. . . . But we no longer take this sort of theo-
rizing very seriously. (Wright 1925, 192)
For the next several decades, environmentalism faded
slowly into the background, although it remained a
strong feature of the journal at least into the 1950s.
Wallace Atwood’s 1934 presidential address (Atwood
1935) cited the need for geographical analysis in adapt-
ing to climate change and its problems for human settle-
ment but stressed adaptability rather than determinism,
calling on geographers to push the federal government

out of its isolationism, to foster international peace and
disarmament, and to help stamp out the “damnable
practices of war” (15).
Human geography of the 1930s and 1940s took one
of three general approaches. The Sauerian approach,
much the dominant, maintained the concept of region
as a central tenet but focused on the influence of culture
in forming the characteristics of regions, with a gradual
swing away from Barrows’s notion of humans adapt-
ing to environment (Whitbeck 1928, 1929; see also
Whittlesey 1945) to a focus on human agency (Doerr
and Guernsey 1956) with many variations in between.
Sauer articulated his approach most forcefully in his
1940 presidential address:
Human geography, then, unlike psychology and history, is
a science that has nothing to do with individuals but only
with human institutions, or cultures. It may be defined
as the problem of the Standort or localization of ways of
living. There are then two methods of approach, one by
the study of the areal extension of individual culture traits
and one by the determination of culture complexes as
areas. (Sauer 1941, 7)
Years later, in another presidential address, Sauer was
to change his view somewhat, as he lamented the
lack of human morality in despoiling nature and urged
People, Place, and Region: 100 Years of Human Geography in
the Annals 1097
geographers to address their concerns to human behav-
ior (Sauer 1956).

The second approach, an attempt to understand hu-
man beings from the point of view that geography is a
product of human imagination, or “geosophy” as Wright
(1925, 12) called it, “the geographical ideas, both true
and false, of all manner of people,” received little at-
tention until the humanistic movement of the 1970s,
although the writings of Ralph H. Brown (1941), John
Leighly (1958), and Clarence Glacken (1960) provide
remarkable exceptions. I return to this approach in due
course.
A third approach to human geography, also rooted
in regional geography, omitted human beings per se to
focus on the distribution of human products, especially
products of economic activities. The first, early contri-
bution in the Annals to what would become known as
urban-economic geography was from Mark Jefferson, who
wrote on the emergence of the American urban system
as an organism responding to environmental conditions
(Jefferson 1915). Over the next two decades, urban-
economic geography became much more systematic in
the attempt to understand location, patterns of distri-
bution, and the transformation of urban landscapes into
functional systems. This approach includes early works
by Platt (1926, 1927, 1934) and Hartshorne (1927).
By the time of his 1945 presidential address, however,
Platt (1946)—recently returned from having spent the
war years in the Office of Strategic Services—had devel-
oped a much more comprehensive and antideterminist
view of the discipline (see also Platt 1948). In one of the
most thoughtful presidential addresses of the century,
he described geography as the study of “the interlocking
of human lives over the whole earth” (2). He discussed
the “microgeography” of a small section of Illinois in re-

lation to “world unity and disunity, coherence and inco-
herence, attachment and detachment, conjunction and
separation, interdependence and independence” (11).
Reflecting on the war, nuclear weapons, and the public
role of the geographer, he concluded:
Nevertheless the problem is still with us, of dealing with
individual human beings, understanding their immediate
surroundings, and safeguarding the values of local life and
cultural variety. . . . The problem is rooted in a permanent
characteristic of human life, the social and physical local-
ness of human beings in distinct and different localities.
(Platt 1948, 11–12)
The postwar Annals reflected rapid social and politi-
cal change. As Barnes and Farish (2006, 821) pointed
out recently:
Shifting language and practice of regional geography, from
catchall description to an instrumental science, provide a
guide through the thickets of Cold War scholarship, and
suggest a means to locate the work of a Hartshorne or an
Ullman in the realm of encounter that Andrew Picker-
ing (1995) calls “the mangle”—in this case the vast and
complex one set messily in the [Cold War]. (a “mangle”
referring to the intense entanglement of political and ide-
ological issues)
The conversion of the concept of the region into a sys-
tematic unit based on a science of “space,” they claimed
was a deeply ideological response to Cold War priorities.
In any case, the depiction of geography as a disci-
pline of peace disappears from (or is avoided) in the
Annals for a couple of decades, and human geography
scholarship became more starkly divided between a sys-

tematic/quantitative and a descriptive/traditionalist ap-
proach to the discipline. Ironically, both approaches
remained strongly tied to the notion of the region,
notwithstanding argument over what the term means.
Fred Schaefer (1953) described the discipline as residing
in two methodological camps: the systematic and the
regional, the first deriving from the likes of Humboldt
and Ritter and the second from Hettner. He lamented
that “the present conditions of the field indicate a stage
of development, well known from other social sciences,
which finds most geographers still busy with classifica-
tions rather than looking for laws” (Schaefer 1953, 232).
A second problem for Schaefer was with exceptional-
ism, which he attributed initially to Kant and later on
to Hartshorne (1939) as the attitude that geography is
exceptional in its synthetic approach to regions3: “Ge-
ography is a name for a description of nature and the
whole world. Geography and history together fill up the
entire area of our perception: geography that of space
and history that of time” (Kant 1892, 6–8, quoted in
Schaefer 1953, 232). He concluded that geographers
must join other social sciences in the search for sys-
tematic laws—spatial laws—or risk the demise of the
discipline.
Schaefer died before his article was published. It was
read at an annual meeting of the AAG posthumously.
Hartshorne, whose discussion of the nature of geog-
raphy was deemed important enough to merit nearly
500 pages of the journal by editor Derwent Whittlesey
(Hartshorne 1939), issued an irate rejoinder in a let-
ter published in the Annals in 1954 and in an article
a year later, citing “false representations and accusa-
tions” that he set out to correct, laying out ten method-
ological rules, to show that the accusation of excep-
tionalism was baseless (Hartshorne 1955). Later still,

1098 Kobayashi
he cited the consistency of all the German “fathers”
of the discipline—Kant, Humboldt, Ritter, Hettner,
and Schluter—in adopting a chorological approach to
science, based on the areal or spatial association of
things but incorporating both nomothetic and ideo-
graphic principles. Geography, he claimed, “requires
the use of two markedly different methods of study,
the systematic examination of certain categories of re-
lationships over the world or any large part of it, in
general or systematic geography; and the study of the
totality of interrelated phenomena in particular areas,
in special or regional geography” (Hartshorne 1958,
108). Notwithstanding debate about his definition of
the discipline, Hartshorne’s influence cannot be under-
estimated in strengthening an empiricist approach to
the discipline, even throughout the years in which many
geographers sought theoretical, quantitative models.
Meanwhile, Edward Ullman warned against going
too far in the search for general laws about human
conditions, claiming that geography had already been
“burned” by environmental determinism. Instead we
should be concerned with “middle range” theories that
can be mapped, according to the principles of space and
spatial interaction:
By spatial interaction I mean actual, meaningful, human
relations between areas on the earth’s surface, such as the
reciprocal relations and flows of all kinds among industries,
raw materials, markets, culture, and transportation—not
static location as indicated by latitude, longitude, type

of climate, etcetera, nor assumed relations based on in-
adequate data and a priori assumptions. (Ullman 1953,
56)
Ullman stated a general consensus among Annals con-
tributors of the decade that notwithstanding the degree
of systematization, geography is fundamentally regional.
But, warned Trewartha (1953, 111) in a plea for popu-
lation geography, “regional analysis of a superior quality
requires the highest type of mature scholarship and is
not to be undertaken by amateurs.” Trewartha’s address
should also be noted for its influence in establishing
“population geography” as a major stream within the
discipline.
In any case, the pages of the Annals during the 1950s
and 1960s display what Stephen B. Jones (1954, 111)
called the “current urge for theory in geography,” in
advancing a “unified field theory” for political geogra-
phy. Emrys Jones (1956) weighed in for understanding
the laws of “cause and effect.” Others advanced “game
theory” (Gould 1963), and there emerged a significant
number of increasingly sophisticated economic location
theories, reflecting ideas of neoclassical economics (e.g.,
Harris 1954), including “central place theory” (Mayfield
1963; Morrill 1963) and stochastic processes (Harvey
1966). Brian Berry summed up this era—in which hu-
man geographers seemed to forget the “human” in favor
of systems—by appealing to “systems theory” and stated
three principles that for him defined the discipline: (1)
“Geographers are, like any other scientists, identified not
so much by the phenomena they study, as by the integrat-
ing concepts and processes that they stress”; (2) “The geo-
graphic point of view is spatial”; and (3) “The integrating
concepts and processes of the geographer relate to spatial

arrangements and distributions, to spatial integration, to
spatial interactions and organization, and to spatial process”
(Berry 1964, 2–3; italics in original). There followed
the development of increasingly complex models, us-
ing analogy to depict the geographies of a “large and
multivariate reality” (Chorley 1964, 127). Geographers
sought explanation in “economic man” (Wolpert 1964)
and “probability theory” (Clark 1965). Even the most
abstract of quantitative geographers, however, could ob-
serve that:
Whether history is lawful is a matter for those who write
it to decide. That spatial processes occur, to which the
historian could not contribute understanding but which
are the very stuff of geography, appears self-evident—or at
least a worthy article of faith. (Curry 1964, 146)
As the 1960s drew to a close, the Annals published sev-
eral more classics based on modeling economic geogra-
phy (Morrill and Pitts 1967; Clark 1968; Cox 1968;
Golledge and Amedeo 1968; Huff and Jenks 1968;
Brown and Longbrake 1970) during a period charac-
terized by what Clyde Kohn (1970) called the “new
social geography.”4
At the same time, under Joseph Spencer’s, and later
John Hudson’s, editorship, cultural and historical geog-
raphy advanced rich studies along the Sauerian tradi-
tion, including Mikesell’s (1967) discussion of cultural
geography and its relations with anthropology through
cultural ecology; Kniffen’s (1965) study of house types
as an exercise in moving from classification (Kniffen
1936) to a theory of cultural diffusion; Logan’s (1968)
study of the boundary as an influence on landscape for-
mation; Miller’s (1968) wonderfully evocative account
of the relationship between folk tales and ways of life

in the Ozarks; and Hilliard’s (1969) innovative study
of variations in pork consumption and regional eco-
nomics in the antebellum South. The city emerged as
a place of dynamic social relations in David Ward’s
(1968) description of immigrant settlement. Brunn and
the Annals 1099
Hoffman (1970) showed an increasing attention to nu-
anced spatial variations in human behavior, in one of
the first articles to address differences between blacks
and whites in the United States.
The Annals of the 1960s, during what Peter Gould
(1979) called the “Augean period,” was a showcase for
a new generation of human geographers: brash, curi-
ous, intellectually demanding of themselves and their
discipline, making strong claims for the power of sci-
ence, and seeking more and more complex ways to un-
derstand geography as a spatial science. As the 1970s
rolled around, contributions to the Annals began to re-
flect a larger concern for geography’s role in society, re-
sponding to larger societal concerns about the ongoing
Vietnam War, the advent of activism over environmen-
tal degradation, the second-wave feminist movement,
and the burgeoning human rights movement. Reflect-
ing these social concerns, the new, radical journal An-
tipode had started up in 1969, and it had garnered a small
but dedicated following, especially among graduate stu-
dents (“Past Editors’ Reflections” n.d.). Les King was to
reflect on the 1970s as a period of “disillusionment and
consolidation” due in large part to a growing recognition
of “a symbiotic relationship between quantitative geog-

raphy and the planning and control of society” (King
1979, 155). He noted that even such thinkers as Edward
Taaffe, whom he described as “spokesman for those of
us of the liberal establishment” (156) recognized a need
for change. Taaffe’s 1973 presidential address called for
a “cautious and pragmatic pluralism, maintaining the
three traditions of human geography” (which he called
“man–land relationships,” “areal study,” and “spatial or-
ganization”), but warning:
We can no longer afford the exuberant confidence in cur-
rent theories, models, and techniques which dismisses val-
ues, societal utility, and the existence of alternative paths
to Rome, including essentially verbal and essentially pre-
scriptive paths. (Taaffe 1974, 12)
A perusal of the book review section of the Annals for
the early 1970s reflects these comments in a plethora
of publications about American cities. Terms such as
blight and decay abounded, along with comments on
contemporary issues such as health care, migration, and
urban well-being and an increasing number of articles
on urban poverty and housing quality (Hartshorn 1971;
Meyer 1973).
Theoretically, two paths towards social relevance
emerge from the 1970s’ Annals, one broadly labeled
humanistic and the other Marxist. Humanistic geogra-
phy was represented by a series of trendsetting articles
that began a decade earlier with David Lowenthal’s
(1961) tour de force on the geographical imagination,
linking apperception, memory, and epistemology. By
1974, the concept of “place” had gained increasing
interest. Leonard Guelke (1974) advocated dialectical
idealism as a philosophical approach to the rationality

of human thought and behavior in place. Ley and
Cybriwsky’s (1974) powerful ethnography of urban
graffiti in Baltimore addressed the relationship between
place and human attitudes, styles, and aspirations.
Robert Sack (1976) used “magic” to explore the
historical emergence of beliefs—and doubts—about
human spatial experience. Tuan (1976, 267) laid out
a sweeping mandate for humanistic geography as the
study of “articulated geographical ideas.” Buttimer
(1976) explored the dynamism of the phenomenolog-
ical concept of the “life world” for understanding the
relationship between human being and place. Entrikin
(1976) pointed out that contemporary ideas of human-
ism might best be understood as a form of philosophical
criticism rather than as an understanding of the world:
Reaffirming the importance of the study of meaning and
value in human geography, making geographers aware of
their often extreme interpretations of science . . . [but] one
of a number of means by which geographers can be made
more self-aware and cognizant of many of the hidden as-
sumptions and implications of their methods and research.
(632)
In 1976, John Leighly paid tribute to two important
predecessors to the new humanism and its epistemolog-
ical rigor in a review of a book in tribute to John K.
Wright:
In recent years American academic geographers have been
paying a great deal of attention to subjective notions, in
their soul-searching sometimes coming perilously close to
omphaloskepsis [a.k.a. navel-gazing]. Knowledge of sub-
jective notions concerning the actual or even an imaginary
world, however, as the authors of Geographies of the Mind
amply demonstrate without undue introspection, can con-

tribute to appreciation of the real world. (Leighly 1976,
655)
Leighly wrote another piece in the same volume to
commemorate Carl Sauer, who had died in 1975. He
used the opportunity to describe how Sauer—and pre-
sumably Leighly himself—found “distasteful” what he
viewed as a narrow and economistic bent in recent ge-
ographical scholarship. Leighly’s vision of geography,
and his support of recent developments in humanistic
geography, were thus clearly normative, as was Mike-
sell’s presidential address of 1977 (Mikesell 1978), in
1100 Kobayashi
which he stressed the importance of the “tradition”
of cultural geography established by Sauer and others,
while also lauding the “innovation” of what he termed
recent studies in “environmental perception.” These
commentaries by Leighly, Mikesell, and others marked
an important transition in human, and especially cul-
tural, geography. James Duncan (1980) summed up that
transition at the end of the 1970s, responding directly
to Mikesell’s call to consider more seriously how geogra-
phers theorize culture, by claiming that earlier cultural
geographers had separated the individual from a su-
perorganic notion of culture, based on transcendental
holism.5 Attention to the ontological status of both in-
dividuals and their cultural products, claimed Duncan,
would provide for a better analysis of social conditions.
In analyzing social conditions, the 1980s established
a number of important new—or at least deepened—
foci for human geographers. One important thread is

in structuration theory, in which place is a “constantly
becoming human product” (Pred 1984) or a basis for
a philosophically pragmatic understanding of the re-
lationship between place and human action (Smith
1984). Another thread addressed the power of ideology,
including that of the state, to influence the character of
place (Harvey 1979; Anderson 1987). All these works
were significant precursors to the geographies of differ-
ence that were to characterize the end of the century
and to which I return momentarily.
Although it garnered far fewer pages in the Annals
during the early years, Marxian geography was of no less
importance. The first Annals piece written from a Marx-
ist perspective was Dick Peet’s article on inequality and
poverty, which argued:
the Marxist principle that inequality and poverty are
inevitably produced by capitalist societies, and the
social-geographic idea that inequality may be passed on
from one generation to the next via the environment of
opportunities and services into which each individual is
implanted at birth. (Peet 1975, 564)
In the issue commemorating the seventy-fifth anniver-
sary of the AAG, however, the Marxist tradition re-
ceived significant coverage. James Blaut claimed that
the “dissenting tradition” in geography came about be-
cause of a disciplinary neglect, or the inability to address
important historical issues: “The cultural geography of
nationalism; . . . [and] the historical geography of colo-
nialism. When these two projects have been completed,
the priorities will change again. I will get back to the
study of children” (Blaut 1979, 164). Blaut never did get
back to the study of children. In the same volume, Peet

accounted for the rise of Marxist geography because “the
practical applications of geography became increasingly
irrelevant as societal contradictions intermeshed” (Peet
1979, 166). Moreover, Marxist geography represented
some of the most sophisticated theorizing about the re-
lationship between the social and the spatial (e.g., Soja
1980). After seventy-five years, ideology and politics
had become explicit rather than implicit in the Annals.
In his 1981 presidential address, John Fraser Hart
lamented the influence of “scientism” in geography.
No doubt by then a majority of the discipline agreed
with him about the problems of narrow, systematic
spatialism, although some of the best scholarship in
the Annals continued to develop increasingly com-
plex analyses of exceedingly complex social issues. He
called for a return to regional geography as the “high-
est form of the geographer’s art” (Hart 1982). On that
issue few agreed, but geographers were beginning to
take seriously Les King’s (1979) call for dialogue be-
tween so-called humanistic and Marxist geographies.
Many were skeptical. In his 1983 presidential address,
Richard Morrill (1984) warned against both and the
problems inherent in allowing politics to stand in the
way of truth, although he cited potential nuclear war
as an example of a threat to the earth that surpassed
all political consideration. Morrill’s comments were
no doubt in part influenced by controversy that had
erupted over the publication a year earlier of Jim Dun-
can and David Ley’s (1982) critique of structural Marx-
ism in geography. They cited the work of Peet, Blaut,
Harvey, and others (much of this work published in
Antipode, although several articles, Peet [1975, 1979];
Harvey [1979], were published in the Annals). Ruth
Fincher and Vera Chouinard responded with a charge
that Duncan and Ley’s interpretation was too narrow

and ignored the many interpretations of Marx, includ-
ing humanistic Marxism (“Comment in reply” 1983), to
which Duncan and Ley replied that humanistic Marx-
ism had had remarkably little presence in human ge-
ography. Notwithstanding the futility of this particular
debate, it signaled a serious and important conversation
that has developed in the pages of the Annals over ques-
tions of structuralism or, more accurately, the existence
of structures, which led the way to a poststructuralist
paradigm that came to dominate human geography of
the 1990s and beyond.
Broadly, poststructuralism refers to a range of theoret-
ical perspectives that recognize structure as a historical
product; that is, a product of human action, or labor.
Poststructuralists therefore refute notions of environ-
mental determinism, both in its Darwinian forms and
the Annals 1101
in explanations that locate determinants somewhere
in spatial laws. They also refute notions that human
beings are hard-wired, a priori, to exhibit determined
characteristics. Although many variants of poststruc-
turalism can be discerned in the pages of the Annals
from the 1980s onward, an overall theme is a con-
vergence of thinking between so-called Marxists and
humanists (although I do not want to exaggerate this
convergence or reduce one to the other). The most
important result of poststructuralism, with its emphasis
on human social outcomes, has been recognition of the
importance of studying the ways that human beings,
including geographers, create difference through social,

cultural, political, and economic practices.6
To this point I have said almost nothing about gen-
der, feminism, or women geographers. Against great
odds, women had made a significant contribution to the
discipline over the century, but as Jan Monk described
in her presidential address of 2003 (Monk 2004), their
presence was grudgingly accepted, their work marginal-
ized, and their numbers—and their writings—few. We
can speculate on the practices at work, but the fact is
that writing by or about women was not the stuff of the
Annals. There are few notable exceptions of women
whose work was considered scholarly enough for pub-
lication. They include Ellen Churchill Semple (e.g.,
Semple 1919), who published a total of five substan-
tial articles in the Annals; Helen Strong (1925, 1937);
Mildred Berman (1965, 1971); and Hildegard Binder
Johnson (1957), all of whom believed in sound field re-
search as a basis for writing the geography of the world.
Jan Monk’s presidential address publicly acknowledged
the extent to which women’s contributions to the dis-
cipline had been underestimated.
Research about gender, however, was slow in
coming. The first article to take seriously the social
effects of gender differences was John Everitt’s (1976)
analysis of propinquity, friendship, and cognitive
spatial relationships in Los Angeles. As far as I can tell,
the first words in the Annals from a feminist perspective
were in two book reviews by Suzanne Mackenzie, who,
with exquisite understatement, claimed that “gender
studies and feminist scholarship are among the most
prolific and dynamic areas of contemporary academic
discourse, but are also among the most ambivalent and
problematic for the academy” (Mackenzie 1985, 609).
Later, she directed geographers to a book by sociologists:

Not only does it contribute to the growing body of
work that recognizes the importance of studying human–
environmental relations in all social sciences, it provides
some interesting ideas about how we might do such studies
within geography. (Mackenzie 1987, 304)
The first full article using feminist analysis was Susan
Hanson and Geraldine Pratt’s “Job Search and the Oc-
cupational Segregation of Women” (Hanson and Pratt
1991). In Hanson’s 1992 presidential address, she made
a strong case for the importance of feminist research to
human geography:
Any attempt to make sense of the world as if it were
ungendered is, in a feminist’s view . . . to risk undertaking
a fundamentally flawed analysis. This particular idea has
not, until recently, flourished in geography, which instead
has focused on place, space, and location as key organiz-
ing concepts and has dealt with each . . . as if it were com-
pletely ungendered (and unclassed and unraced). (Hanson
1992, 569)
Hanson made a direct call to study the human propen-
sity to create difference, strong words for a disci-
pline in which—notwithstanding increasing attention
to class—“race” and gender had received scant atten-
tion. The main form of differentiation was areal. More
recently, in her 2006 presidential address, Victoria
Lawson (2007) extended the discussion of the role
of feminism to emphasize that geography includes an
ethics of care and responsibility.
Until the turn of the twenty-first century, there was
negligible space in the Annals devoted to scholarship

from a feminist or an antiracist perspective. Environ-
mentalism, of course, had often clothed overt racism in
science, but human geographers were slow to counter
the claims of racial difference, explicit or implicit, turn-
ing instead to systemic processes, including culture, as
the basis for geographic explanation. It is surprising
nonetheless that as late as 1968 the Annals published
an article written from an avowedly racial science per-
spective (de Laubenfels 1968; cf. Carlson and Armela-
gos 1971). In contrast, throughout the 1970s and 1980s,
the Annals published many articles on the problems cre-
ated by racial segregation, especially in American inner
cities. The attention to “race” differs thus substantially
from the inattention to gender, but theoretical debates
on the nature of “race” came much later. Peet (1985)
claimed that geographers had followed social Darwin-
ism rather than Marxism, thus legitimating a science
of racism that spatial science had done little if any-
thing to counter. It took the intersection of feminist
and antiracist geographers, however, along the lines
that Hanson suggested in 1991, to establish in geogra-
phy a “politics of difference” that sheds essentialist no-
tions of gender and race and class and extends notions
1102 Kobayashi
of racism to include the cultural politics of difference
(Gilbert 1998; Kobayashi and Peake 2000; Nast 2000;
Pulido 2000; Hoelscher 2003).
If feminism and antiracism represent two examples of
new approaches to human geography at the turn of the
millennium, they occur within a wider context of
geography that addresses the big ways in which the

world is changing. Geographical perspectives on
change are increasingly sophisticated and none could
accuse this discipline of lack of relevance. Some of the
best examples of scholarship from the 1990s and the
early twenty-first century (and I apologize that this is
more of a shopping list than a critical examination of
the ideas) include Jones and Kodras’s (1990) discussion
of the feminization of poverty; Don Mitchell’s (1995)
path-breaking investigation of the use of “public space”
in San Francisco; Denis Cosgrove’s (2003) erudite
account of the emergence of cosmopolitanism; Ellis,
Wright, and Parks’s (2004) sophisticated analysis of
“race,” gender, and home and workplace segregation;
John Agnew’s (2005) ambitious discussion of territori-
ality and the state; Jason Dittmer’s (2005) creative take
on popular culture, identity, and politics; and Steve
Herbert’s (2005) thoughtful and challenging piece on
the vaunted notion of community.
What to conclude about 100 years of human geogra-
phy in the Annals? In his 2001 presidential address, Reg
Golledge (2002) commented that what marks geogra-
phy at the end of the twentieth century is “a change from
inventory dominated activity to the creation of knowl-
edge generated by emphasizing cognitive demands, such
as understanding ‘why’ and ‘how’ in addition to ‘what’
and ‘where”’ (1). I have attempted here to recognize
some of the articles that have advanced the “why” and
“how” of human geography and the ways in which ge-
ographers have used the pages of the Annals to debate
the mandate and scope of our discipline. Geographers
over the century have developed an increasingly com-
plex understanding of economic, political, social, and
cultural processes that help to explain the relationship
between people and place in many different parts of
the world, and current scholarship is enhanced by rig-

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