LETTERS

Sufficient-cause
Interaction
To the Editor:
he conditions required to prove the
presence of sufficient-cause interaction using the coefficients from a loglinear model with 2 binary exposures have
previously been described by VanderWeele.1 We broaden the conditions and
derive easy-to-remember criteria such as:
If the product of the separate relative
risks is greater than or equal to their sum,
testing for 3 0 implies sufficient-cause
interaction and The interaction term on
the relative risk scale should be larger than
the sum of the separate relative risks divided by their product. The criteria presented here are especially important for
judging sufficient-cause interaction when
the relative risk of the interaction term is
below unity (a negative interaction term
on the logarithmic scale).
VanderWeele1 derived conditions
for sufficient-cause interactions in a saturated log-linear model for the probability
of the outcome (D) as a function of 2
binary determinants (X1 and X2):

ADAPTED DERIVATION
To derive the conditions for
which a test for statistical interaction, 3
0, in the log-linear model corresponds
to a test for a sufficient-cause interaction, VanderWeele rewrote the above
formula as:
12e123 e 1 12e123
e2 0
By using, rather than the factor
(12), the factors x and (1 x), with x
between 0 and 1, more precise conditions can be obtained for which testing
for 3 0 implies sufficient-cause
interaction. We rewrite VanderWeeles Equation 9 as:
123

xe

123

e 1 xe
2

e 0 where 0 x 1.

ally, the conditions for 3 0 to imply

sufficient-cause interaction become:

3 log1/x 2 and
3 log1/1 x 1
As 1 log(RR10) and 2
log(RR01) this leads to
RR01 1/x and RR10 1/1 x
where 0 x 1

(2)

Note that x 12 yields the conditions: RR01 2 and RR10 2, as obtained by VanderWeele. However, when x
is chosen to be equal to 1/RR01, the second part of condition (2) becomes:
RR10 1/1 1/RR01
which can be rewritten as:

(1)

Detailed
derivations
are
reported
in
eAppendix
1
(http://links.lww.com/EDE/A409). Eventu-

RR01 RR10 RR01 RR10

(3)

(see
eAppendix
1,
http://links.lww.com/EDE/A409). This

logPD 1 X1 x1 , X2 x2
0 1 x1 2 x2 3 x1 x2
Based on this model and without
assuming monotonicity of the effects
of X1 and X2 on D, the most general
condition for the presence of sufficient-cause interaction is:
e0123 e01 e02 0 or
e123 e1 e2 0
(the latter being VanderWeeles Equation 91).
From this, minimal values of 1
and 2 can be derived for which a test
for statistical interaction (3 0) implies sufficient-cause interaction.
Supplemental digital content is available
through direct URL citations in the
HTML and PDF versions of this article
(www.epidem.com).

FIGURE. Minimal values of RR10 and RR01, to show sufficient-cause interaction, for
different values of 3. Each curve represents a different value of 3 (values shown
in the right margin). From each curve, the minimal values of RR10 and RR01 at
which sufficient-cause interaction is proven can be read. Higher values of RR10 and
RR01, above the curves, also show sufficient cause interaction. The upper right
square shows the RR10 2 and RR01 2-area initially indicated by VanderWeele,
for 3 0.

Epidemiology Volume 21, Number 5, September 2010

www.epidem.com | 753

Epidemiology Volume 21, Number 5, September 2010

Letters

leads to the easy-to-remember rule that:

If the product of separate relative risks
is greater than or equal to their sum,
testing for 3 0 implies sufficientcause interaction.
An alternative way to derive this
rule is by rewriting VanderWeeles 9 as:

1. VanderWeele TJ. Sufficient cause interactions and statistical interactions. Epidemiology. 2009;20:6 13.

which is equal to:

e 1 e 2
1

e e

(4)

If now: e e 2 e 1 e 2
and 3 0, condition (4) is satisfied, leading to the same rule as from condition (3).
In general, condition (4) can be
written as:

e 3

RR10 RR01
RR10 RR01

(5)

This leads to the other easy-toremember rule that the interaction term
on the relative risk scale should be
larger than the sum of the separate relative risks divided by their product.
The minimum values for RR10 and
RR01 to indicate sufficient-cause interaction for different 3 are represented in the
Figure. Sufficient-cause interaction is
present in the area above the curves. Our
conditions cover more than VanderWeeles RR10 2 and RR01 2, as is
shown in the Figure. If one of the relative
risks is large, the other can be even smaller
than 2. For instance, with RR10 6, and
RR01 1.2, 3 0 still implies sufficient-cause interaction. In the case of
monotonicity of the effects of X1 and X2
on D, the required adaptations will make it
even easier to fulfill the conditions.
We expand our reasoning to
3-way interaction in eAppendix 2
(http://links.lww.com/EDE/A409).

ACKNOWLEDGMENTS
We thank Saskia le Cessie, Jan Vandenbroucke, and Tyler VanderWeele for
critical discussion of previous drafts.
754 | www.epidem.com

Rutger A. Middelburg
Department of Epidemiology
Leiden University Medical Center
Leiden, The Netherlands

REFERENCE

e 3e 1 e 2 e 1 e 2 0

Leo M. G. van de Watering

Sanquin Blood Bank Southwest region
Leiden, The Netherlands
l.vandewatering@sanquin.nl

Diabetes Mellitus in
Rural India
To the Editor:
o investigate the prevalence of diabetes mellitus in a typical rural society, we performed a population-based
study in rural Central India. We included
2414 subjects aged 30 years or more. Diabetes was defined as postprandial blood
glucose concentration 200 mg/dL, glycosylated hemoglobin 6%, or self-reported medical diagnosis. The prevalence
of diabetes (5.6% 0.5%) increased up to
the age of 60 to 64 years and decreased
thereafter.
Despite the worldwide importance
of diabetes mellitus, relatively little has
been known about its actual prevalence
and its associations in India, particularly in
rural India.1 6 The Central India Eye and
Medical Study is a population-based
cross-sectional study in Central India. The
first phase was carried out in 4 villages in
the rural region of Central Maharashtra
about 40 km from Nagpur.7 The villages
were chosen because they are in a typical
rural region of Central India, relatively far
from the nearest city. The Medical Ethics
Committee of the Ruprecht-Karls-University Heidelberg and of the Suraj Eye In-

Supported by an unrestricted grant from Om

Drishti Trust Nagpur; Heidelberg Engineering
Co. Heidelberg, Germany; Rotary Sight Saver
Netherlands; Orbis India; and Carl Zeiss Meditec Co., Jena, Germany.
Copyright 2010 by Lippincott Williams &
Wilkins
ISSN: 1044-3983/10/2105-0754
DOI: 10.1097/EDE.0b013e3181e66201

stitute/Nagpur approved the study, and all

participants gave informed consent. Social
workers mapping the villages invited villagers to participate in the study. Participation included a bus ride to and from the
hospital, a day-long free examination, and
free meals out of 3093 eligible villagers,
2423 (78%) subjects participated. Trained
social workers filled out a questionnaire.
Physical activity was assessed by questions about the daily working time, daily
walking or cycling to work, time spent
sitting or reclining, and whether the work
involved mostly sitting or standing activities. Diabetes was defined as a postprandial blood glucose concentration 11.2
mmol/L (200 mg/dL a blood concentration of glycosylated hemoglobin (Hb1Ac)
of 6%, or a self-reported medical diagnosis of diabetes (any prior diagnosis of
diabetes by a health care professional).
Treatment of diabetes was defined as use
of prescribed medication for management
of diabetes (oral medication or insulin) at
the time of the interview. Successful control of diabetes was defined as pharmacologic treatment of diabetes associated with
a postprandial blood glucose concentration of 11.2 mmol/L (200 mg/dL) and
an Hb1Ac level of 7%.
Of the 2423 subjects, 789 (33%)
were illiterate and 645 (27%) had attended school up to the fifth standard.
Women comprised 54% of the study
population. The distribution of the study
population by age and sex was almost
identical to that of India as a whole.8
Measurements of postprandial
blood glucose and Hb1Ac were available
for 2414 (99%) of study participants).
Mean age was 48.0 13.7 years (median,
45 years; range, 30 85 years). The mean
postprandial blood glucose concentration
was 118 29 mg/mL, and the mean
blood concentration of glycosylated hemoglobin Hb1Ac was 4.6% 1.6%. A
self-reported diagnosis of diabetes was
given by 34 (1.4%) subjects. Out of these
34 subjects, 13 (38%) patients were on
oral antidiabetic treatment, 2 (6%) subjects took insulin, 11 (32%) subjects were
not aware of their treatment regimen, and
8 (24%) subjects were treated by diet only.
2010 Lippincott Williams & Wilkins

Epidemiology Volume 21, Number 5, September 2010

Letters

Department of Ophthalmology
Medical Faculty Mannheim of the
Ruprecht-Karls-University Heidelberg
Mannheim, Germany

Vinay Nangia
Suraj Eye Institute
Nagpur, Maharashtra
India
nagpursuraj@gmail.com

Prashant P. Joshi
Clinical Epidemiology Unit
Govt. Medical College
Nagpur, India

Arshia Matin
Suraj Eye Institute
Nagpur, Maharashtra
India
FIGURE. Prevalence of diabetes mellitus in the population of the Central India Eye and
Medical Study, stratified by age.

Of 2414 subjects, we diagnosed 135

(5.6%) as patients with diabetes. Prevalence of diabetes was similar for men and
women, and rose with age in both.
In univariate analysis, the prevalence of diabetes increased with age
(Fig.), body weight, and body mass index. Prevalence was increased with
higher mean serum concentrations of
cholesterol, lower concentration of highdensity lipoproteins, less physical activity, more time spent sitting or reclining,
and more hyperopic refractive error.
In multiple logistic regression analysis, the association of diabetes persisted
with higher age (odds ratio 1.03 per
year [95% confidence interval 1.01
1.04), higher body mass index (1.14
1.09 1.19), higher serum cholesterol
levels (1.01 1.011.02), and lower serum high-density lipoprotein concentration (0.93 0.89 0.97).
Among the diabetic study participants (n 135), 34 (25%) subjects were
aware of their disease, and 15 (11%) reported a current antidiabetic medical treatment. Out of the treated subjects, 7 (47%)
had abnormally high postprandial glucose
levels, and 6 (40%) had Hb1Ac measurements equal to or higher than 7%.
DISCUSSION
In the rural population of Central India,
we found evidence of diabetes in 5.6%
2010 Lippincott Williams & Wilkins

0.5% of subjects aged 30 years. This

figure is lower than previously reported in
urban Indian populations.2 6 The relationship of age with diabetes prevalence followed an inverted U-shape with a decrease toward higher age. The lack of
major medical services, with a potentially
elevated mortality of elderly subjects with
diabetes, may have led to a survivor bias.
After adjustment for age, body mass index, and serum cholesterol levels, there
was little evidence of associations between diabetes and educational level, family income, or physical activities. This is in
contrast with other population-based studies. The reason for this lack of association
may be the relatively low socioeconomic
level of these villagers, with only small
differences in life conditions among the
study population. Among the diabetic
study participants, 25% subjects were
aware of their disease, and 15 (11%) subjects were under treatment. These figures
are markedly lower than those reported from
urban and semi-urban regions in India,26
suggesting that major improvements in medical infrastructure are needed to address this
wide spread condition in India.
Jost B. Jonas
Songhomitra Panda-Jonas
Suraj Eye Institute
Nagpur, Maharashtra
India

REFERENCES
1. Barr EL, Zimmet PZ, Welborn TA, et al. Risk
of cardiovascular and all-cause mortality in
individuals with diabetes mellitus, impaired
fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and
Lifestyle Study (AusDiab). Circulation. 2007;
116:151157.
2. Mohan V, Shanthirani S, Deepa R, Premalatha
G, Sastry NG, Saroja R. Intra-urban differences
in the prevalence of the metabolic syndrome in
southern Indiathe Chennai Urban Population
Study (CUPS No. 4). Diabet Med. 2001;4:280
287.
3. Ramachandran A, Snehalatha C, Baskar AD,
et al. Temporal changes in prevalence of
diabetes and impaired glucose tolerance associated with lifestyle transition occurring in
the rural population in India. Diabetologia.
2004;47:860 865.
4. Menon VU, Kumar KV, Gilchrist A, et al.
Prevalence of known and undetected diabetes
and associated risk factors in central Kerala
ADEPS. Diabetes Res Clin Pract. 2006;74:
289 294.
5. Ramachandran A, Mary S, Yamuna A,
Murugesan N, Snehalatha C. High prevalence
of diabetes and cardiovascular risk factors associated with urbanization in India. Diabetes
Care. 2008;31:893 898.
6. Yajnik CS, Joglekar CV, Lubree HG, et al.
Adiposity, inflammation and hyperglycaemia
in rural and urban Indian men: Coronary Risk
of Insulin Sensitivity in Indian Subjects
(CRISIS) Study. Diabetologia. 2008;51:
39 46.
7. Nangia V, Bhojwani K, Matin A, Sinha A,
Jonas JB. Intraocular pressure and arterial
blood pressure. The Central India Eye and
Medical Study. Arch Ophthalmol. 2009;127:
339 340.
8. National Indian census 2001. Available at: http://
www.censusindia.gov.in/Census_Data_2001/
Projected_Population/Projected_Population.pdf.

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