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A Multivariate Logistic Regression
Equation to Screen for Diabetes
Development and validation
BAHMAN P. TABAEI, MPH
1
WILLIAM H. HERMAN, MD, MPH
1,2
OBJECTIVE — To develop and validate an empirical equation to screen for diabetes.
RESEARCH DESIGN AND METHODS — A predictive equation was developed using
multiple logistic regression analysis and data collected from 1,032 Egyptian subjects with no
history of diabetes. The equation incorporated age, sex, BMI, postprandial time (self-reported
number of hours since last food or drink other than water), and random capillary plasma glucose
as independent covariates for prediction of undiagnosed diabetes. These covariates were based
on a fasting plasma glucose level Ն126 mg/dl and/or a plasma glucose level 2 h after a 75-g oral
glucose load Ն200 mg/dl. The equation was validated using data collected from an independent
sample of 1,065 American subjects. Its performance was also compared with that of recom-
mended and proposed static plasma glucose cut points for diabetes screening.
RESULTS — The predictive equation was calculated with the following logistic regression
parameters: P ϭ 1/(1 Ϫ eϪx
), where x ϭ Ϫ10.0382 ϩ [0.0331 (age in years) ϩ 0.0308 (random
plasma glucose in mg/dl) ϩ 0.2500 (postprandial time assessed as 0 to Ն8 h) ϩ 0.5620 (if
female) ϩ 0.0346 (BMI)]. The cut point for the prediction of previously undiagnosed diabetes
was defined as a probability value Ն0.20. The equation’s sensitivity was 65%, specificity 96%,
and positive predictive value (PPV) 67%. When applied to a new sample, the equation’s sensi-
tivity was 62%, specificity 96%, and PPV 63%.
CONCLUSIONS — This multivariate logistic equation improves on currently recom-
mended methods of screening for undiagnosed diabetes and can be easily implemented in a
inexpensive handheld programmable calculator to predict previously undiagnosed diabetes.
Diabetes Care 25:1999–2003, 2002
S
creening for undiagnosed diabetes is
controversial. In 1978, the Ameri-
can Diabetes Association (ADA), the
Centers for Disease Control and Preven-
tion, and the National Institutes of Health
recommended against screening for dia-
betes in nonpregnant adults (1). In 1989
and again in 1996, the U.S. Preventive
Services Task Force recommended
against screening for diabetes in nonpreg-
nant adults (1,2), and in 2001, the ADA
recommended against community
screening for diabetes (3). Several recent
studies have shown that age, sex, BMI,
and current metabolic status affect blood
glucose levels and have raised concerns
about the performance of diabetes screen-
ing tests (4–8).
The performance of all screening tests
is dependent on the threshold or cut point
used to define a positive test. In diabetes
screening, choosing a higher glucose cut
point reduces sensitivity (probability of a
positive screening test given disease) but
improves specificity (probability of a neg-
ative screening test given absence of dis-
ease). Choosing a lower glucose cut point
improves sensitivity but reduces specific-
ity. Because the optimal cut point for a
positive test may depend on age, sex, BMI,
and the time since last food or drink, we
propose an alternative approach to inter-
preting capillary glucose screening tests
by developing a multivariate equation
using the best combination of readily
available data to predict previously undi-
agnosed diabetes.
RESEARCH DESIGN AND
METHODS — To assess the likeli-
hood of previously undiagnosed diabetes,
a predictive equation was developed us-
ing data from 1,032 Egyptian subjects
without a history of diabetes who partic-
ipated in the Diabetes in Egypt Project
between July 1992 and October 1993 (9).
In a household examination, all subjects
were assessed for age, sex, height, weight,
postprandial time (self-reported number
of hours since last food or drink other
than water), and random capillary whole
blood glucose. On a separate day, fasting
plasma glucose (FPG) and plasma glucose
2 h after a 75-g oral glucose load (2-h PG)
were measured. Multiple logistic regres-
sion analysis was used to develop an
equation for prediction of undiagnosed
diabetes based on FPG Ն126 mg/dl
and/or 2-h PG Ն200 mg/dl. Diabetes risk
factors included in the equation were age
(years), sex (female), BMI (calculated as
weight in kilograms divided by height in
meters squared [kg/m2
]), postprandial
time (0 to Ն8 h), and random capillary
plasma glucose (mg/dl). Age, BMI, and
capillary plasma glucose were modeled as
continuous variables, postprandial time
was modeled as a continuous variable be-
tween 0 and 8 h (after which random cap-
illary glucose did not vary as a function of
postprandial time), and sex was modeled
● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
From the 1
Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan;
and the 2
Department of Epidemiology, University of Michigan Health System, Ann Arbor, Michigan.
Address correspondence and reprint requests to William H. Herman, MD, MPH, University of Michigan
Health System, Division of Endocrinology and Metabolism, 1500 E. Medical Center Dr., 3920 Taubman
Center, Ann Arbor, MI 48109-0354. E-mail: wherman@umich.edu.
Received for publication 21 January 2001 and accepted in revised form 26 June 2002.
Abbreviations: 2-h PG, plasma glucose 2 h after a 75-g oral glucose load; ADA, American Diabetes
Association; EPV, events per variable; FPG, fasting plasma glucose; OAPR, odds of being affected given a
positive result; PPV, positive predictive value; ROC, receiver-operating characteristic.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
O R I G I N A L A R T I C L E
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 1999
as a categorical variable (0 ϭ male and
1 ϭ female). The final mathematical
equation provides an estimate of a sub-
ject’s likelihood of previously undiag-
nosed diabetes expressed as a probability
between 0.0 and 1.0.
The linearity assumption for logistic
regression was assessed by categorizing
each continuous variable into multiple di-
chotomous variables of equal units and
plotting each variable’s coefficient against
the midpoint of the variable. We also per-
formed the Mantel-Haenszel ␹2
test for
trend. Multicollinearity was assessed us-
ing the Pearson correlation coefficient sta-
tistic. Accuracy, reliability, and precision
of regression coefficients were assessed by
calculating the number of events per vari-
able (EPV)—the ratio of the number of
outcome events to the number of predic-
tor variables. An EPV number of at least
10 indicates that the estimates of regres-
sion coefficients and their CIs are reliable
(10,11). The possible interactions among
variables were assessed using the Breslow
and Day ␹2
test (12).
The Ϫ2 log-likelihood ratio test was
used to test the overall significance of the
predictive equation. The significance of
the variables in the model was assessed by
the Wald ␹2
test and CIs. The fit of the
model was assessed by the Hosmer-
Lemeshow goodness of fit ␹2
test (13,14).
To assess outliers and detect extreme
points in the design space, logistic regres-
sion diagnostics were performed by plot-
ting the diagnostic statistic against the
observation number using hat matrix di-
agonal and Pearson and Deviance residu-
als analyses (13,14).
To select the optimal cut point to de-
fine a positive test, a receiver-operating
characteristic (ROC) curve was con-
structed by plotting sensitivity against the
false-positive rate (1 Ϫ specificity) over a
range of cut-point values. Generally, the
best cut point is at or near the shoulder of
the ROC curve, where substantial gains
can be made in sensitivity with only mod-
est reductions in specificity. Sensitivity
was defined as the proportion of subjects
predicted to have the outcome who really
have it (true-positive test) and calculated
as [true positives/(true positives ϩ false
negatives)] ϫ 100. Specificity was de-
fined as the proportion of subjects pre-
dicted not to have the outcome who do
not have it (true-negative test) and calcu-
lated as [true negatives/(true negatives ϩ
false positives)] ϫ 100. Positive predic-
tive value (PPV) was defined as the per-
centage of individuals with a positive test
result who actually have the disease and
was calculated as [true positives/(true
positives ϩ false positives)] ϫ 100. The
odds of being affected given a positive re-
sult (OAPR) was defined as the ratio of the
number of affected to unaffected individ-
uals among those with positive results
and was calculated as true positives/false
positives.
Concordance and discordance val-
ues, derived from the logistic regression
analysis, were used to measure the asso-
ciation of predicted probabilities and
to check the ability of the model to predict
outcome. The higher the value of the con-
cordance and the lower the value of dis-
cordance, the greater the ability of
the model to predict outcome. To evalu-
ate the overall performance of the equa-
tion, we considered several measures of
predictive performance, including dis-
crimination and calibration (15–20). Dis-
crimination was defined as the ability of
the equation to distinguish high-risk sub-
jects from low-risk subjects and is quan-
tified by the area under the ROC curve
(15,19,20). Calibration was defined as
whether the predicted probabilities agree
with the observed probabilities and is
quantified by the calibration slope calcu-
lated as [model ␹2
Ϫ (df Ϫ 1)[/model ␹2
(16,20,21). Well-calibrated models have
a slope of ϳ1, whereas models providing
too extreme of predictions have a slope of
Ͻ1 (17,20).
To validate the equation, we applied
it to data that had not been used to gen-
erate the equation. Thus, we applied the
equation to data collected from 1,065
subjects with no history of diabetes who
were studied between September 1995
and July 1998 by health care systems
serving communities in Springfield, MA;
Robeson County, NC; Providence, Paw-
tucket, RI; and Central Falls, RI (7). All
subjects were assessed for age, sex, height,
weight, postprandial time, random capil-
lary plasma glucose, and, on a separate
day, FPG and 2-h PG.
To compare the results obtained with
the predictive equation and the results
obtained with various recommended and
proposed random capillary plasma glu-
cose cut points, we applied the equation
and those cut points to the combined
Egyptian and American datasets. Capil-
lary plasma glucose values were calcu-
lated by multiplying capillary whole
blood glucose values by 1.14. All statisti-
cal analyses were performed using SAS
software version 6.12 (SAS Institute,
Cary, NC).
RESULTS — Table 1 describes the de-
mographic characteristics of the Egyptian
and American subjects. The American
participants included Hispanics (58%),
non-Hispanic whites (19%), African-
Americans (12%), Native Americans
(4%), and others (7%). The diabetes pre-
dictive equation was calculated with the
following logistic regression parameters:
P ϭ 1/(1 Ϫ eϪx
), where x ϭ Ϫ10.0382 ϩ
[0.0331 (age in years) ϩ 0.0308 (random
plasma glucose in mg/dl) ϩ 0.2500 (post-
prandial time assessed as 0 to Ն8 h) ϩ
0.5620 (if female) ϩ 0.0346 (BMI)]. Ta-
ble 2 shows the maximum likelihood es-
timates for the logistic regression
function. The overall significance of the
equation by the Ϫ2 log-likelihood test
was 299.6 (P ϭ 0.0001) with 5 df, with
89% concordant pairs and 11% discor-
dant pairs. The Hosmer-Lemeshow good-
ness of fit test was 5.27 (P ϭ 0.73) with 8
df. The EPV number was 134/5 ϭ 26.8.
Because no interactions, either alone or in
combination, added significantly to the
equation, we did not add any of these pa-
rameters. No potential outliers were de-
tected, and the equation met the linearity
assumption for logistic regression analysis.
Table 1—Demographic characteristics of the study populations
Variable Egyptian subjects American subjects
n 1,032 1,065
Age (years) 45 Ϯ 14 46 Ϯ 15
Sex (F) 609 (59) 731 (69)*
BMI (kg/m2
) 29.8 Ϯ 7.6 28.4 Ϯ 6.4
Capillary plasma glucose (mg/dl) 124.7 Ϯ 51.8 100.8 Ϯ 24.1*
Postprandial time (0–8ϩ h) 3.2 Ϯ 1.7 4.8 Ϯ 2.9*
Data are means Ϯ SD or n (%). *Statistically significant at P Ͻ 0.0001 vs. Egyptian subjects.
Diabetes screening equation
2000 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
The probability level that provided an
optimal cut point was 0.20. Based on the
classification table, derived from the lo-
gistic regression and ROC curve analysis,
sensitivity was 65%, specificity 96%, and
PPV 67% (Fig. 1). The area under the
ROC curve was 0.88. The calibration
slope was (299.6 Ϫ 4)/299.6 ϭ 0.99.
When applied to a new sample of 1,065
subjects, the equation’s sensitivity was
62%, specificity 96%, and PPV 63%.
These represented relatively small decre-
ments from the original equation.
The diabetes predictive equation per-
formed better than the various proposed
static random capillary plasma glucose
cut points for a positive test when applied
to the combined population with 10%
prevalence of undiagnosed diabetes (the
prevalence observed in the combined
Egyptian and American data sets) (Table
3). In general, the equation yielded higher
sensitivity, identified more new cases
(true positives), and missed fewer new
cases (false negatives) than the static cap-
illary plasma glucose cut points Ն140,
Ն150, Ն160, Ն170, and Ն180 mg/dl.
The equation yielded higher specificity
and identified fewer false-positive cases
than the static capillary plasma glucose
cut points Ն110, Ն120, Ն130, Ն140,
and Ն150 mg/dl. The equation yielded
higher PPV and OAPR than the static cap-
illary plasma glucose cut points Ն110,
Ն120, Ն130, Ն140, Ն150, Ն160, and
Ն170 mg/dl.
CONCLUSIONS — The perfor-
mance of all screening tests depends on
the cut points used to define a positive
test. The choice of a higher cut point
leaves more cases undetected, and the
choice of a lower cut point classifies more
healthy individuals as abnormal (5). Cur-
rently, there are no widely accepted or
rigorously validated cut points to define
positive screening tests for diabetes in
nonpregnant adults (6). The ADA has rec-
ommended a random capillary whole
blood glucose cut point of Ն140 mg/dl
(capillary plasma glucose Ն160 mg/dl),
and Rolka et al. (7) have recommended a
random capillary plasma glucose cut
point of Ն120 mg/dl.
Optimal cut points for random capil-
lary glucose tests depend on age, sex,
BMI, and postprandial time (6,7). Multi-
variate equations incorporate multiple
pieces of diagnostic information and can
provide a flexible alternative to static cut
points for the definition of a positive test
(21). We have developed a multivariate
predictive equation based on age, sex,
BMI, postprandial time, and capillary
plasma glucose levels to assess the likeli-
hood of previously undiagnosed diabetes.
The equation was 65% sensitive and 96%
specific. In validation testing, the equa-
tion was 62% sensitive and 96% specific.
Predictive equations rarely perform as
well with new data as with the data with
which they were developed because dur-
ing development, the equation maximizes
the probability of predicting the values in
the original dataset. When testing an
equation, the important factor is the size
of the decrement in performance. The rel-
atively small decrement in sensitivity and
unchanged specificity suggest that the
equation has both external validity and
generalizability (21).
A decision regarding acceptable levels
of sensitivity and specificity involves
weighting the consequences of leaving
cases undetected (false negatives) and
classifying healthy individuals as abnor-
mal (false positives) (22,23). Like the
ADA-recommended plasma glucose cut
point of 160 mg/dl, the logistic equation
provided high specificity (96%) (Table 3).
Compared with the ADA-recommended
cut point of 160 mg/dl, the logistic equa-
tion improved sensitivity (44 and 63%,
respectively) (Table 3). Compared with
the plasma glucose cut point of 120 mg/dl,
the logistic equation improved specificity
(77 and 96%, respectively) but was less
sensitive (76 and 63%, respectively) (Table
3).
Highly specific screening tests mini-
mize the number of false-positive results
but increase the number of false-negative
results. They are preferable if the failure to
Figure 1—ROC curve. Points on the ROC
curve represent the probability levels generated
from the logistic regression analysis that was
used to select the optimal cut point. A probabil-
ity value of 0.20 provided a sensitivity of 65%
and a specificity of 96%. Sensitivity and speci-
ficity of risk factors for the prediction of previ-
ously undiagnosed diabetes based on FPG
Ն126 mg/dl and/or 2-h PG Ն200 mg/dl were
estimated using the multiple regression model
described in the text, in which FPG and/or 2-h
PG were modeled as a function of age, random
plasma glucose, postprandial time, sex, and
BMI. Screening tests that discriminate well be-
tween diabetic and nondiabetic individuals ag-
gregate toward the upper left corner of the ROC
curve. The area under the curve quantifies how
well the screening test correctly distinguishes a
diabetic from a nondiabetic individual; the
greater the area under the curve, the better the
performance of the screening test. A diagonal
reference line (area under the curve ϭ 0.50)
defines points where a test is no better than
chance in identifying individuals with diabetes.
Table 2—Maximum likelihood estimates of logistic regression function
Variable
Estimated regression
coefficient Estimated SE Wald␹
2 P
Estimated
odds ratio
95% CI for
odds ratio
Intercept Ϫ10.0382 Ϯ0.8123 — 0.0001 — —
Age (years) 0.0331 Ϯ0.009 12.7 0.0004 1.39* 1.16–1.67*
Plasma glucose (mg/dl) 0.0308 Ϯ0.003 101.6 0.0001 1.36* 1.28–1.44*
Postprandial time (0–8 h) 0.2500 Ϯ0.625 16.0 0.0001 1.28† 1.13–1.45
Sex (F) 0.5620 Ϯ0.277 4.1 0.04 1.75 1.02–3.02
BMI (kg/m2
) 0.0346 Ϯ0.014 5.8 0.02 1.04† 1.01–1.07
* Estimated odds ratios and 95% CIs for 10-unit increase; †estimated odds ratios and 95% CIs for 1-unit increase
Tabaei and Herman
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2001
make an early diagnosis and initiate treat-
ment does not have dire health conse-
quences, if a disease is uncommon in the
population, and if false-positive results
can harm the subject physically, emotion-
ally, or financially. Type 2 diabetes is of-
ten slowly progressive and is not
associated with complications in the short
term. Individuals with initial false-
negative screening tests will be identified
as abnormal on rescreening, particularly
if they have progressive glucose intoler-
ance. In addition, undiagnosed diabetes is
uncommon: in a representative sample of
the U.S. population 40–74 years of age,
undiagnosed diabetes, defined by FPG
Ն140 mg/dl or 2-h PG Ն200, was present
in only 6.7% (24). False-positive screen-
ing tests require further diagnostic tests
that are inconvenient, expensive, and
time-consuming. For these reasons, we
believe that the predictive equation,
which is highly specific, is preferable to a
static glucose cut point of 120 mg/dl,
which is much less specific. We also be-
lieve that the predictive equation is pref-
erable to a static glucose cut point of 160
mg/dl because, given comparable high
specificity, it is much more sensitive.
PPV and OAPR are measures of the
performance of a diagnostic test that de-
pend on the prevalence of the disease in
the screened population and on the sen-
sitivity and specificity of the test
(22,25,26). However, unlike sensitivity
and specificity, they are not properties of
the screening test itself, but of its applica-
tion. The multivariate predictive equation
provided a PPV of 64% and an OAPR of
1.75. These results were better than those
obtained with all static plasma glucose cut
points Ͻ180 mg/dl and indicate that
among those with a positive test, 64% ac-
tually have diabetes (true positives), and
the odds of having a true-positive test re-
sult are 1.75 times greater than the odds
of having a false-positive result (Table 3).
Tests with an OAPR Ͻ1 identify fewer
true positives than false positives.
In summary, by incorporating rele-
vant risk factor data, the predictive equa-
tion performs better in the general
population than any single glucose cut
point. The multivariate equation can be
implemented with a number of inexpen-
sive, programmable, handheld calcula-
tors. We programmed the formula and
coefficients presented in RESEARCH DESIGN
AND METHODS into a TI-83 graphic and sci-
entific calculator (Texas Instruments,
Dallas, TX). To obtain a probability value,
the user enters the values for age (years),
capillary plasma glucose (mg/dl), post-
prandial time (0 to Ն8 h), BMI (kg/m2
),
and sex (0 ϭ male and 1 ϭ female). The
calculator prompts the user by displaying
the coefficient for the variable that should
be entered next. The result displayed is
the calculated probability that a subject
has previously undiagnosed diabetes (a
number between 0.0 and 1.0). The pro-
gramming is available on request. Using
this device and a glucose meter, a health
care professional can perform a quick
point-of-care assessment of the probabil-
ity of undiagnosed diabetes in either a
public health or clinical setting.
Acknowledgments— This work was sup-
ported by the U.S. Agency for International
Development and the Egyptian Ministry of
Health under PASA (Participating Agency Ser-
vice Agreement) 236-0102-P-HI-1013-00, the
Michigan Diabetes Research and Training
Center under grant DK-20572, and the Cen-
ters for Disease Control and Prevention.
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meyer H-M, Byrd-Holt DD: Prevalence of
diabetes, impaired fasting glucose, and
impaired glucose tolerance in U.S. adults.
Diabetes Care 21:518–524, 1998
25. Greenberg RS, Daniels SR, Flanders WD,
Eley JW, Boring JR III: Medical Epidemiol-
ogy. New York, McGraw Hill, 2001
26. Cuckle HS, Wald N: Tests using single
markers. In Antenatal and Neonatal Screen-
ing. 2nd ed. Wald N, Leck I, Eds. Oxford,
U.K., Oxford University Press, 2000, p.
3–22
Tabaei and Herman
DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2003

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1999.full

  • 1. A Multivariate Logistic Regression Equation to Screen for Diabetes Development and validation BAHMAN P. TABAEI, MPH 1 WILLIAM H. HERMAN, MD, MPH 1,2 OBJECTIVE — To develop and validate an empirical equation to screen for diabetes. RESEARCH DESIGN AND METHODS — A predictive equation was developed using multiple logistic regression analysis and data collected from 1,032 Egyptian subjects with no history of diabetes. The equation incorporated age, sex, BMI, postprandial time (self-reported number of hours since last food or drink other than water), and random capillary plasma glucose as independent covariates for prediction of undiagnosed diabetes. These covariates were based on a fasting plasma glucose level Ն126 mg/dl and/or a plasma glucose level 2 h after a 75-g oral glucose load Ն200 mg/dl. The equation was validated using data collected from an independent sample of 1,065 American subjects. Its performance was also compared with that of recom- mended and proposed static plasma glucose cut points for diabetes screening. RESULTS — The predictive equation was calculated with the following logistic regression parameters: P ϭ 1/(1 Ϫ eϪx ), where x ϭ Ϫ10.0382 ϩ [0.0331 (age in years) ϩ 0.0308 (random plasma glucose in mg/dl) ϩ 0.2500 (postprandial time assessed as 0 to Ն8 h) ϩ 0.5620 (if female) ϩ 0.0346 (BMI)]. The cut point for the prediction of previously undiagnosed diabetes was defined as a probability value Ն0.20. The equation’s sensitivity was 65%, specificity 96%, and positive predictive value (PPV) 67%. When applied to a new sample, the equation’s sensi- tivity was 62%, specificity 96%, and PPV 63%. CONCLUSIONS — This multivariate logistic equation improves on currently recom- mended methods of screening for undiagnosed diabetes and can be easily implemented in a inexpensive handheld programmable calculator to predict previously undiagnosed diabetes. Diabetes Care 25:1999–2003, 2002 S creening for undiagnosed diabetes is controversial. In 1978, the Ameri- can Diabetes Association (ADA), the Centers for Disease Control and Preven- tion, and the National Institutes of Health recommended against screening for dia- betes in nonpregnant adults (1). In 1989 and again in 1996, the U.S. Preventive Services Task Force recommended against screening for diabetes in nonpreg- nant adults (1,2), and in 2001, the ADA recommended against community screening for diabetes (3). Several recent studies have shown that age, sex, BMI, and current metabolic status affect blood glucose levels and have raised concerns about the performance of diabetes screen- ing tests (4–8). The performance of all screening tests is dependent on the threshold or cut point used to define a positive test. In diabetes screening, choosing a higher glucose cut point reduces sensitivity (probability of a positive screening test given disease) but improves specificity (probability of a neg- ative screening test given absence of dis- ease). Choosing a lower glucose cut point improves sensitivity but reduces specific- ity. Because the optimal cut point for a positive test may depend on age, sex, BMI, and the time since last food or drink, we propose an alternative approach to inter- preting capillary glucose screening tests by developing a multivariate equation using the best combination of readily available data to predict previously undi- agnosed diabetes. RESEARCH DESIGN AND METHODS — To assess the likeli- hood of previously undiagnosed diabetes, a predictive equation was developed us- ing data from 1,032 Egyptian subjects without a history of diabetes who partic- ipated in the Diabetes in Egypt Project between July 1992 and October 1993 (9). In a household examination, all subjects were assessed for age, sex, height, weight, postprandial time (self-reported number of hours since last food or drink other than water), and random capillary whole blood glucose. On a separate day, fasting plasma glucose (FPG) and plasma glucose 2 h after a 75-g oral glucose load (2-h PG) were measured. Multiple logistic regres- sion analysis was used to develop an equation for prediction of undiagnosed diabetes based on FPG Ն126 mg/dl and/or 2-h PG Ն200 mg/dl. Diabetes risk factors included in the equation were age (years), sex (female), BMI (calculated as weight in kilograms divided by height in meters squared [kg/m2 ]), postprandial time (0 to Ն8 h), and random capillary plasma glucose (mg/dl). Age, BMI, and capillary plasma glucose were modeled as continuous variables, postprandial time was modeled as a continuous variable be- tween 0 and 8 h (after which random cap- illary glucose did not vary as a function of postprandial time), and sex was modeled ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1 Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan; and the 2 Department of Epidemiology, University of Michigan Health System, Ann Arbor, Michigan. Address correspondence and reprint requests to William H. Herman, MD, MPH, University of Michigan Health System, Division of Endocrinology and Metabolism, 1500 E. Medical Center Dr., 3920 Taubman Center, Ann Arbor, MI 48109-0354. E-mail: wherman@umich.edu. Received for publication 21 January 2001 and accepted in revised form 26 June 2002. Abbreviations: 2-h PG, plasma glucose 2 h after a 75-g oral glucose load; ADA, American Diabetes Association; EPV, events per variable; FPG, fasting plasma glucose; OAPR, odds of being affected given a positive result; PPV, positive predictive value; ROC, receiver-operating characteristic. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 1999
  • 2. as a categorical variable (0 ϭ male and 1 ϭ female). The final mathematical equation provides an estimate of a sub- ject’s likelihood of previously undiag- nosed diabetes expressed as a probability between 0.0 and 1.0. The linearity assumption for logistic regression was assessed by categorizing each continuous variable into multiple di- chotomous variables of equal units and plotting each variable’s coefficient against the midpoint of the variable. We also per- formed the Mantel-Haenszel ␹2 test for trend. Multicollinearity was assessed us- ing the Pearson correlation coefficient sta- tistic. Accuracy, reliability, and precision of regression coefficients were assessed by calculating the number of events per vari- able (EPV)—the ratio of the number of outcome events to the number of predic- tor variables. An EPV number of at least 10 indicates that the estimates of regres- sion coefficients and their CIs are reliable (10,11). The possible interactions among variables were assessed using the Breslow and Day ␹2 test (12). The Ϫ2 log-likelihood ratio test was used to test the overall significance of the predictive equation. The significance of the variables in the model was assessed by the Wald ␹2 test and CIs. The fit of the model was assessed by the Hosmer- Lemeshow goodness of fit ␹2 test (13,14). To assess outliers and detect extreme points in the design space, logistic regres- sion diagnostics were performed by plot- ting the diagnostic statistic against the observation number using hat matrix di- agonal and Pearson and Deviance residu- als analyses (13,14). To select the optimal cut point to de- fine a positive test, a receiver-operating characteristic (ROC) curve was con- structed by plotting sensitivity against the false-positive rate (1 Ϫ specificity) over a range of cut-point values. Generally, the best cut point is at or near the shoulder of the ROC curve, where substantial gains can be made in sensitivity with only mod- est reductions in specificity. Sensitivity was defined as the proportion of subjects predicted to have the outcome who really have it (true-positive test) and calculated as [true positives/(true positives ϩ false negatives)] ϫ 100. Specificity was de- fined as the proportion of subjects pre- dicted not to have the outcome who do not have it (true-negative test) and calcu- lated as [true negatives/(true negatives ϩ false positives)] ϫ 100. Positive predic- tive value (PPV) was defined as the per- centage of individuals with a positive test result who actually have the disease and was calculated as [true positives/(true positives ϩ false positives)] ϫ 100. The odds of being affected given a positive re- sult (OAPR) was defined as the ratio of the number of affected to unaffected individ- uals among those with positive results and was calculated as true positives/false positives. Concordance and discordance val- ues, derived from the logistic regression analysis, were used to measure the asso- ciation of predicted probabilities and to check the ability of the model to predict outcome. The higher the value of the con- cordance and the lower the value of dis- cordance, the greater the ability of the model to predict outcome. To evalu- ate the overall performance of the equa- tion, we considered several measures of predictive performance, including dis- crimination and calibration (15–20). Dis- crimination was defined as the ability of the equation to distinguish high-risk sub- jects from low-risk subjects and is quan- tified by the area under the ROC curve (15,19,20). Calibration was defined as whether the predicted probabilities agree with the observed probabilities and is quantified by the calibration slope calcu- lated as [model ␹2 Ϫ (df Ϫ 1)[/model ␹2 (16,20,21). Well-calibrated models have a slope of ϳ1, whereas models providing too extreme of predictions have a slope of Ͻ1 (17,20). To validate the equation, we applied it to data that had not been used to gen- erate the equation. Thus, we applied the equation to data collected from 1,065 subjects with no history of diabetes who were studied between September 1995 and July 1998 by health care systems serving communities in Springfield, MA; Robeson County, NC; Providence, Paw- tucket, RI; and Central Falls, RI (7). All subjects were assessed for age, sex, height, weight, postprandial time, random capil- lary plasma glucose, and, on a separate day, FPG and 2-h PG. To compare the results obtained with the predictive equation and the results obtained with various recommended and proposed random capillary plasma glu- cose cut points, we applied the equation and those cut points to the combined Egyptian and American datasets. Capil- lary plasma glucose values were calcu- lated by multiplying capillary whole blood glucose values by 1.14. All statisti- cal analyses were performed using SAS software version 6.12 (SAS Institute, Cary, NC). RESULTS — Table 1 describes the de- mographic characteristics of the Egyptian and American subjects. The American participants included Hispanics (58%), non-Hispanic whites (19%), African- Americans (12%), Native Americans (4%), and others (7%). The diabetes pre- dictive equation was calculated with the following logistic regression parameters: P ϭ 1/(1 Ϫ eϪx ), where x ϭ Ϫ10.0382 ϩ [0.0331 (age in years) ϩ 0.0308 (random plasma glucose in mg/dl) ϩ 0.2500 (post- prandial time assessed as 0 to Ն8 h) ϩ 0.5620 (if female) ϩ 0.0346 (BMI)]. Ta- ble 2 shows the maximum likelihood es- timates for the logistic regression function. The overall significance of the equation by the Ϫ2 log-likelihood test was 299.6 (P ϭ 0.0001) with 5 df, with 89% concordant pairs and 11% discor- dant pairs. The Hosmer-Lemeshow good- ness of fit test was 5.27 (P ϭ 0.73) with 8 df. The EPV number was 134/5 ϭ 26.8. Because no interactions, either alone or in combination, added significantly to the equation, we did not add any of these pa- rameters. No potential outliers were de- tected, and the equation met the linearity assumption for logistic regression analysis. Table 1—Demographic characteristics of the study populations Variable Egyptian subjects American subjects n 1,032 1,065 Age (years) 45 Ϯ 14 46 Ϯ 15 Sex (F) 609 (59) 731 (69)* BMI (kg/m2 ) 29.8 Ϯ 7.6 28.4 Ϯ 6.4 Capillary plasma glucose (mg/dl) 124.7 Ϯ 51.8 100.8 Ϯ 24.1* Postprandial time (0–8ϩ h) 3.2 Ϯ 1.7 4.8 Ϯ 2.9* Data are means Ϯ SD or n (%). *Statistically significant at P Ͻ 0.0001 vs. Egyptian subjects. Diabetes screening equation 2000 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
  • 3. The probability level that provided an optimal cut point was 0.20. Based on the classification table, derived from the lo- gistic regression and ROC curve analysis, sensitivity was 65%, specificity 96%, and PPV 67% (Fig. 1). The area under the ROC curve was 0.88. The calibration slope was (299.6 Ϫ 4)/299.6 ϭ 0.99. When applied to a new sample of 1,065 subjects, the equation’s sensitivity was 62%, specificity 96%, and PPV 63%. These represented relatively small decre- ments from the original equation. The diabetes predictive equation per- formed better than the various proposed static random capillary plasma glucose cut points for a positive test when applied to the combined population with 10% prevalence of undiagnosed diabetes (the prevalence observed in the combined Egyptian and American data sets) (Table 3). In general, the equation yielded higher sensitivity, identified more new cases (true positives), and missed fewer new cases (false negatives) than the static cap- illary plasma glucose cut points Ն140, Ն150, Ն160, Ն170, and Ն180 mg/dl. The equation yielded higher specificity and identified fewer false-positive cases than the static capillary plasma glucose cut points Ն110, Ն120, Ն130, Ն140, and Ն150 mg/dl. The equation yielded higher PPV and OAPR than the static cap- illary plasma glucose cut points Ն110, Ն120, Ն130, Ն140, Ն150, Ն160, and Ն170 mg/dl. CONCLUSIONS — The perfor- mance of all screening tests depends on the cut points used to define a positive test. The choice of a higher cut point leaves more cases undetected, and the choice of a lower cut point classifies more healthy individuals as abnormal (5). Cur- rently, there are no widely accepted or rigorously validated cut points to define positive screening tests for diabetes in nonpregnant adults (6). The ADA has rec- ommended a random capillary whole blood glucose cut point of Ն140 mg/dl (capillary plasma glucose Ն160 mg/dl), and Rolka et al. (7) have recommended a random capillary plasma glucose cut point of Ն120 mg/dl. Optimal cut points for random capil- lary glucose tests depend on age, sex, BMI, and postprandial time (6,7). Multi- variate equations incorporate multiple pieces of diagnostic information and can provide a flexible alternative to static cut points for the definition of a positive test (21). We have developed a multivariate predictive equation based on age, sex, BMI, postprandial time, and capillary plasma glucose levels to assess the likeli- hood of previously undiagnosed diabetes. The equation was 65% sensitive and 96% specific. In validation testing, the equa- tion was 62% sensitive and 96% specific. Predictive equations rarely perform as well with new data as with the data with which they were developed because dur- ing development, the equation maximizes the probability of predicting the values in the original dataset. When testing an equation, the important factor is the size of the decrement in performance. The rel- atively small decrement in sensitivity and unchanged specificity suggest that the equation has both external validity and generalizability (21). A decision regarding acceptable levels of sensitivity and specificity involves weighting the consequences of leaving cases undetected (false negatives) and classifying healthy individuals as abnor- mal (false positives) (22,23). Like the ADA-recommended plasma glucose cut point of 160 mg/dl, the logistic equation provided high specificity (96%) (Table 3). Compared with the ADA-recommended cut point of 160 mg/dl, the logistic equa- tion improved sensitivity (44 and 63%, respectively) (Table 3). Compared with the plasma glucose cut point of 120 mg/dl, the logistic equation improved specificity (77 and 96%, respectively) but was less sensitive (76 and 63%, respectively) (Table 3). Highly specific screening tests mini- mize the number of false-positive results but increase the number of false-negative results. They are preferable if the failure to Figure 1—ROC curve. Points on the ROC curve represent the probability levels generated from the logistic regression analysis that was used to select the optimal cut point. A probabil- ity value of 0.20 provided a sensitivity of 65% and a specificity of 96%. Sensitivity and speci- ficity of risk factors for the prediction of previ- ously undiagnosed diabetes based on FPG Ն126 mg/dl and/or 2-h PG Ն200 mg/dl were estimated using the multiple regression model described in the text, in which FPG and/or 2-h PG were modeled as a function of age, random plasma glucose, postprandial time, sex, and BMI. Screening tests that discriminate well be- tween diabetic and nondiabetic individuals ag- gregate toward the upper left corner of the ROC curve. The area under the curve quantifies how well the screening test correctly distinguishes a diabetic from a nondiabetic individual; the greater the area under the curve, the better the performance of the screening test. A diagonal reference line (area under the curve ϭ 0.50) defines points where a test is no better than chance in identifying individuals with diabetes. Table 2—Maximum likelihood estimates of logistic regression function Variable Estimated regression coefficient Estimated SE Wald␹ 2 P Estimated odds ratio 95% CI for odds ratio Intercept Ϫ10.0382 Ϯ0.8123 — 0.0001 — — Age (years) 0.0331 Ϯ0.009 12.7 0.0004 1.39* 1.16–1.67* Plasma glucose (mg/dl) 0.0308 Ϯ0.003 101.6 0.0001 1.36* 1.28–1.44* Postprandial time (0–8 h) 0.2500 Ϯ0.625 16.0 0.0001 1.28† 1.13–1.45 Sex (F) 0.5620 Ϯ0.277 4.1 0.04 1.75 1.02–3.02 BMI (kg/m2 ) 0.0346 Ϯ0.014 5.8 0.02 1.04† 1.01–1.07 * Estimated odds ratios and 95% CIs for 10-unit increase; †estimated odds ratios and 95% CIs for 1-unit increase Tabaei and Herman DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2001
  • 4. make an early diagnosis and initiate treat- ment does not have dire health conse- quences, if a disease is uncommon in the population, and if false-positive results can harm the subject physically, emotion- ally, or financially. Type 2 diabetes is of- ten slowly progressive and is not associated with complications in the short term. Individuals with initial false- negative screening tests will be identified as abnormal on rescreening, particularly if they have progressive glucose intoler- ance. In addition, undiagnosed diabetes is uncommon: in a representative sample of the U.S. population 40–74 years of age, undiagnosed diabetes, defined by FPG Ն140 mg/dl or 2-h PG Ն200, was present in only 6.7% (24). False-positive screen- ing tests require further diagnostic tests that are inconvenient, expensive, and time-consuming. For these reasons, we believe that the predictive equation, which is highly specific, is preferable to a static glucose cut point of 120 mg/dl, which is much less specific. We also be- lieve that the predictive equation is pref- erable to a static glucose cut point of 160 mg/dl because, given comparable high specificity, it is much more sensitive. PPV and OAPR are measures of the performance of a diagnostic test that de- pend on the prevalence of the disease in the screened population and on the sen- sitivity and specificity of the test (22,25,26). However, unlike sensitivity and specificity, they are not properties of the screening test itself, but of its applica- tion. The multivariate predictive equation provided a PPV of 64% and an OAPR of 1.75. These results were better than those obtained with all static plasma glucose cut points Ͻ180 mg/dl and indicate that among those with a positive test, 64% ac- tually have diabetes (true positives), and the odds of having a true-positive test re- sult are 1.75 times greater than the odds of having a false-positive result (Table 3). Tests with an OAPR Ͻ1 identify fewer true positives than false positives. In summary, by incorporating rele- vant risk factor data, the predictive equa- tion performs better in the general population than any single glucose cut point. The multivariate equation can be implemented with a number of inexpen- sive, programmable, handheld calcula- tors. We programmed the formula and coefficients presented in RESEARCH DESIGN AND METHODS into a TI-83 graphic and sci- entific calculator (Texas Instruments, Dallas, TX). To obtain a probability value, the user enters the values for age (years), capillary plasma glucose (mg/dl), post- prandial time (0 to Ն8 h), BMI (kg/m2 ), and sex (0 ϭ male and 1 ϭ female). The calculator prompts the user by displaying the coefficient for the variable that should be entered next. The result displayed is the calculated probability that a subject has previously undiagnosed diabetes (a number between 0.0 and 1.0). The pro- gramming is available on request. Using this device and a glucose meter, a health care professional can perform a quick point-of-care assessment of the probabil- ity of undiagnosed diabetes in either a public health or clinical setting. Acknowledgments— This work was sup- ported by the U.S. Agency for International Development and the Egyptian Ministry of Health under PASA (Participating Agency Ser- vice Agreement) 236-0102-P-HI-1013-00, the Michigan Diabetes Research and Training Center under grant DK-20572, and the Cen- ters for Disease Control and Prevention. References 1. Herron CA: Screening in diabetes melli- tus: report of the Atlanta workshop. Dia- betes Care 2:357–362, 1979 2. U.S. Preventive Services Task Force: Guide to Clinical Preventive Services: Screening for Diabetes Mellitus. 2nd ed. Baltimore, MD, Williams and Wilkins, 1996, p. 193–208 3. American Diabetes Association: Screening for diabetes (Position Statement). Diabetes Care 24 (Suppl. 1):S21–S25, 2001 4. Engelgau MM, Aubert RE, Thompson TJ, Herman WH: Screening for NIDDM in nonpregnant adults: a review of princi- ples, screening tests, and recommenda- tions. Diabetes Care 18:1601–1618, 1995 5. Engelgau MM, Thompson TJ, Herman WH, Boyle JP, Aubert RE, Kenny SJ, Bad- ran A, Sous ES, Ali MA: Comparison of fasting and 2-hour glucose and HbA1c lev- els for diagnosing diabetes: diagnostic cri- teria and performance revisited. Diabetes Care 20:785–791, 1997 6. Engelgau MM, Nayaran KMV, Herman WH: Screening for type 2 diabetes. Diabe- tes Care 23:1563–1580, 2000 7. Rolka DB, Nayaran KMV, Thompson TJ, Goldman D, Lindenmayer J, Alich K, Ba- call D, Benjamin EM, Lamb B, Stuart DO, Engelgau MM: Performance of recom- mended screening tests for undiagnosed diabetes and dysglycemia. Diabetes Care 24:1899–1903, 2001 8. Engelgau MM, Thompson TJ, Smith PJ, Herman WH, Aubert RE, Gunter EW, Wetterhall SF, Sous ES, Ali MA: Screening for diabetes mellitus in adults. Diabetes Table 3—Comparison of the performance of the predictive equation and static capillary plasma glucose cut points Screening test Sensitivity (%) Specificity (%) PPV (%) OAPR True positive False positive False negative Equation 63 96 64 1.75 63 36 37 Capillary plasma glucose Ն110 mg/dl 84 65 21 0.27 84 315 16 Ն120 mg/dl 76 77 27 0.37 76 207 24 Ն130 mg/dl 63 87 35 0.54 63 117 37 Ն140 mg/dl 55 92 43 0.76 55 72 45 Ն150 mg/dl 50 95 53 1.11 50 45 50 Ն160 mg/dl 44 96 55 1.22 44 36 56 Ն170 mg/dl 42 97 60 1.56 42 27 58 Ն180 mg/dl 39 98 68 2.17 39 18 61 True positive ϭ new cases ϭ prevalence ϫ sensitivity ϫ n; false positive ϭ 1 Ϫ prevalence ϫ 1 Ϫ specificity ϫ n; false negative ϭ missed cases ϭ prevalence ϫ 1-sensitivity ϫ n, where prevalence of undiagnosed diabetes is 10% and n ϭ 1,000. Diabetes screening equation 2002 DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002
  • 5. Care 18:463–466, 1995 9. Herman WH, Ali MA, Aubert RE, Engel- gau MM, Kenny SJ, Gunter EW, Ma- larcher AM, Brechner RJ, Wetterhall SF, DeStefano F, Thompson TJ, Smith PJ, Badran A, Sous ES, Habib M, Hegazy M, abd el Shakour S, Ibrahim AS, el Moneim el Behairy A: Diabetes mellitus in Egypt: risk factors and prevalence. Diabet Med 12:1126–1131, 1995 10. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR: A simulation study of the number of events per variable in lo- gistic regression analysis. J Clin Epidemiol 12:1373–1379, 1996 11. Bagley SC, White H, Golomb BA: Logistic regression in the medical literature: stan- dards for use and reporting, with particu- lar attention to one medical domain. J Clin Epidemiol 54:979–985, 2001 12. SAS Institute Inc.: SAS/STAT User’s Guide, Version 6. Vol. 2., 4th ed., Cary, NC, SAS Institute Inc., 1990 13. SAS Institute Inc.: SAS/STAT software: changes and enhancements through re- lease 6.12. Cary, NC, SAS Institute Inc., 1997 14. Hosmer DW, Lemeshow S: Applied Logis- tic Regression. 2nd ed. New York, Wiley, 2000 15. Steyerberg EW, Harrell FE Jr, Borsboom GJJM, Eijkemans MJC, Vergouwe Y, Habbema JDF: Internal validation of pre- dictive models: efficiency of some proce- dures for logistic regression analysis. J Clin Epidemiol 54:774–781, 2001 16. Altman DG, Royston P: What do we mean by validating a prognostic model? Stat Med 19:453–473, 2000 17. Steyerberg EW, Eijkemans MJC, Harrell FE Jr, Habbema JDF: Prognostic model- ling with logistic regression analysis: a comparison of selection and estimation methods in small data sets. Stat Med 19: 1059–1079, 2000 18. Harrell FE Jr, Lee KL, Mark DB: Multiva- riable prognostic models: issues in devel- oping models, evaluating assumptions and adequacy, and measuring and reduc- ing errors. Stat Med 15:361–387, 1996 19. Justice AC, Covinsky KE, Berlin JA: As- sessing the generalizability of prognostic information. Ann Intern Med 130:515– 524, 1999 20. Steyerberg EW, Eijkemans MJC, Hou- welingen JC, Lee KL, Habbema JD: Prog- nosyic models based on literature and individual patient data in logistic regres- sion analysis. Stat Med 19:141–160, 2000 21. Katz MH: Multivariable Analysis: A Practi- cal Guide for Clinicians. Cambridge, U.K., Cambridge University Press, 1999 22. Fletcher RH, Fletcher SW, Wagner EH: Clinical Epidemiology: The Essentials. 3rd ed. Baltimore, MD, Williams and Wilkins, 1996 23. Hennekens CH, Buring JE: Epidemiology in Medicine. Boston, MA, Little Brown, 1987 24. Harris MI, Flegal KM, Cowie CC, Eber- hardt MS, Goldstein DE, Little RR, Wied- meyer H-M, Byrd-Holt DD: Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. Diabetes Care 21:518–524, 1998 25. Greenberg RS, Daniels SR, Flanders WD, Eley JW, Boring JR III: Medical Epidemiol- ogy. New York, McGraw Hill, 2001 26. Cuckle HS, Wald N: Tests using single markers. In Antenatal and Neonatal Screen- ing. 2nd ed. Wald N, Leck I, Eds. Oxford, U.K., Oxford University Press, 2000, p. 3–22 Tabaei and Herman DIABETES CARE, VOLUME 25, NUMBER 11, NOVEMBER 2002 2003