Journal of Clinical Epidemiology 56 (2003) 956–962

Optimal choice of a cut point for a quantitative diagnostic test

performed for research purposes
Laurence S. Magdera,b,*, Alan D. Fixa
a
Department of Epidemiology and Preventive Medicine, University of Maryland, 660 West Redwood Street, Baltimore, MD 21201, USA
b
Department of Mathematics and Statistics, University of Maryland, Baltimore, MD, USA
Accepted 11 May 2003

Abstract
Often, in epidemiologic research, classification of study participants with respect to the presence of a dichotomous condition (e.g.,
infection) is based on whether a quantitative measurement exceeds a specified cut point. The choice of a cut point involves a tradeoff
between sensitivity and specificity. When the classification is to be made for the purpose of estimating risk ratios (RRs) or odds ratios
(ORs), it might be argued that the best choice of cut point is one that maximizes the precision of estimates of the RRs or ORs. In this article,
two different approaches for estimating RRs and ORs are discussed. For each approach, formulae are derived that give the mean squared
error of the RR and OR estimates, for any choice of cut point. Based on these formulae, a cut point can be chosen that minimizes the
mean squared error of the estimate of interest. 쑖 2003 Elsevier Inc. All rights reserved.
Keywords: Epidemiologic methods; Sensitivity and specificity; Diagnostic tests; Misclassification; Odds ratio; Risk ratio; Study design

1. Introduction Methods for choosing a cut point have been developed

Often, in epidemiologic research designed to estimate the
association between risk factors and a disease, the classifica-
tion of a person with respect to the presence or absence of
disease is based on whether some quantitative measurement
exceeds a specified cut point. This classification is generally
not perfectly accurate, and the choice of the cut point in-
volves a tradeoff between sensitivity and specificity. De-
creasing the value of the cut point results in higher sensitivity,
but lower specificity of the diagnostic test. This article con-
cerns the question of how to choose a cut point in that
context.
For example, there is current interest in estimating the
degree of association between various risk factors (e.g.,
sexual activity) and seropositivity for Herpes Simplex Virus
8 (HSV8). The degree of association can be quantified by
risk ratios (RRs) or odds ratios (ORs). The classification of
study participants with respect to HSV8 seropositivity is
based on whether the value of the optical density of a sero-
logic assay exceeds a specified cut point. Unfortunately,
no matter what cut point is chosen, the assay does not result
in perfectly accurate classifications of HSV8. What would
be the optimal cut point in this context?
* Corresponding author. Tel.: 410-706-3253; fax: 410-706-8013.
E-mail address: Lmagder@epi.umaryland.edu (L.S. Magder).
0895-4356/03/$ – see front matter 쑖 2003 Elsevier Inc. All rights reserved.
doi: 10.1016/S0895-4356(03)00153-7
for the situation in which the test is to be used for diagnosis
in a clinical setting where treatment decisions will be based
on the test results [1]. In this context, the choice of cut point
should be based on the consequences of treating those who
do not have the condition, the consequences of failing to treat
those who do have the condition, and the prevalence of the
condition in question [1]. This approach can be implemented
by plotting an receiver operating characteristic (ROC) curve
and finding the point on the curve at which the slope equals
[C/B][(1⫺pD)/pD] where C is the net cost of treating someone
without the condition, B is the net benefit of treating
someone with the condition, and pD is the patient’s pretest
probability of having the disease [1].
However, when the test is used for research purposes and
treatment decisions are not based on the test results, the
choice of the cut point should be based on scientific consider-
ations. Specifically, if the test is to be used in epidemiologic
research to estimate RRs and ORs, it might be argued that
a cut point should be chosen that results in the most precise
RR and OR estimates.
In this article, we consider two general approaches for
estimating RRs and ORs and for each approach we provide
formulae that can be used to calculate the precision of
the estimates for any choice of cut point. Based on these
formulae, cut points can be chosen that result in the best
estimates. Throughout, it is assumed that the sensitivity and
specificity of the diagnostic test are known at each possible
 L.S. Magder, A.D. Fix / Journal of Clinical Epidemiology 56 (2003) 956–962
cut point. However, the results have implications for choos-
ing cut points when there is uncertainty about the sensitivity
and specificity of the test at each cut point.
2. Statement of the problem
For linguistic simplicity, we will use the words “disease” to
refer to the health condition of interest, and “exposure”
to refer to a dichotomous risk factor. Let Z stand for the
quantitative variable used to classify people with respect to
the presence or absence of disease. The usefulness of Z
for classifying people depends on the degree to which the
distribution of Z among those with disease differs from
the distribution of Z among those without disease. Fig. 1
illustrates hypothetical distributions of Z among the diseased
and the nondiseased. In this illustration, the two distributions
are both normal with standard deviation equal to 1, but with
means that differ by three standard deviations. The horizontal
axis is labeled with respect to the distance from the mean
of Z in the nondiseased.
To classify people as diseased or nondiseased based on
an observed value of Z, a cut point is chosen. If the value
of Z for a person exceeds the cut point, then the person is
classified as diseased (test result positive). Otherwise, the
person is classified as nondiseased (test result negative).
The two shaded areas in Fig. 1 illustrate the sensitivity
(shaded area on the right) and specificity (shaded are on the
left) that would result if a cut point of 2.0 were chosen.
Fig. 1. Illustration of hypothetical distributions of Z among the diseased (right curve) and undiseased (left curve). The area in the shaded region to the
right of 2.0 represents the sensitivity that would result if 2.0 was chosen as the cut point. The area in the shaded region to the left of 2.0 represents
the specificity that would result.
957
How should we choose the value of the cut point when the
classification is being made strictly for research purposes?
We would argue that the a cut point should be chosen
that maximizes the precision of estimates of scientific interest.
Here, we consider the cases in which the goal is to estimate
RRs or ORs. More precisely, let pD|E and pD|Ē stand for
the probability of disease among the exposed and unexposed
respectively. In these terms,
RR ⫽ pD|E ÷ pD|Ē
and
OR ⫽ pD|E/(1⫺pD|E) ÷ pD|Ē/(1⫺pD|Ē).
To quantify the precision of an estimate, it is common
to use the mean squared error (MSE), the average squared
distance between an estimate and the true value [2]. The
MSE is equal to the variance of the estimate plus the square
of the bias of the estimate. To determine the precision of
estimates of the RR and the OR it is common and convenient
to work on the log scale. Thus, the precision of an estimate
of RR, say RR̂, can be quantified using
MSE ⫽ Expected value of (logRR̂ ⫺ logRR)2
⫽ Var(logRR̂) ⫹ (bias(logRR̂))2.
The analogous expression is used for the OR. Given an
estimation approach, the problem reduces to finding the cut
point that minimizes the MSE.
958 L.S. Magder, A.D. Fix / Journal of Clinical Epidemiology 56 (2003) 956–962
3. Choosing a cut point when the RR or OR
will be estimated in a standard manner
We assume independent observations are available from
n study subjects. For each subject, information regarding
the presence or absence of the exposure and the value of Z
is known. Given such data, there are several approaches to
estimating the RR and OR.
The standard approach would be to choose a cut point,
classify the subjects with respect to disease based on this
cut point, and estimate the RR or OR as if these classifica-
tions represented the true disease status of each person. To
describe this approach more precisely, notation is provided
in Table 1. This represents a hypothetical two-by-two table
that can be constructed once a cut point for the quantita-
tive measurement Z is chosen.
Using the notation in Table 1, let p̂T⫹|E ⫽ a/nE and
p̂T⫹|Ē ⫽ c/nĒ denote the standard estimates of the probability
of testing positive for the disease given exposure and nonex-
posure respectively. The standard approach to estimating the
RR and the OR in this setting is to use
RR̂standard ⫽ p̂T⫹|E/p̂T⫹|Ē
and
OR̂standard ⫽ (p̂T⫹|E/(1⫺p̂T⫹|E)) ÷ (p̂T⫹|Ē/(1⫺p̂T⫹|Ē)).
Appendix A contains formulas for the asymptotic vari-
ance and bias of these estimates derived using the “delta
method” [3]. No assumptions were needed to derive these
formulae other than the availability of independent observa-
tions and knowledge of the sensitivity and specificity of
the test. In particular, the formulae do not depend on the
normality of Z. As can be seen, the variance and bias depend
on: (1) the sample size among exposed and unexposed, (2)
the true values of pD|E and pD|Ē, and (3) the sensitivity and
specificity of the diagnostic test. Given these values, we can
calculate the MSE of the estimates.
Now we assume that the sensitivity and specificity are
known for each possible cut point under consideration.
Therefore, given sample sizes and values of pD|E and pD|Ē
we can calculate the MSE of these estimates at each possible
cut point under consideration and then choose the cut point
that leads to the lowest MSE. In actuality, we will not know
the true values of pD|E and pD|Ē, but substituting our best
guesses for them will result in the best guess regarding the
optimal cut point.
Table 1
Notation for cell counts in two-by-two tables
Classification of study participants based
on the diagnostic test
Classified as diseased Classified as nondiseased
Exposed a b
Unexposed c d
To illustrate the results of applying these formulae, we
consider the special case in which the distribution of Z
among both the diseased and nondiseased is normal with
the same variance but different means. Fig. 2a–d shows the
MSE of the standard estimates calculated at a range of cut
points under various scenarios. Fig. 2b and d is based on two
distributions whose means are separated by three standard
deviations, as illustrated in Fig. 1. The horizontal axes con-
sists of an interval of possible cut points, labeled by their
distance (in standard deviations) from the mean of the distri-
bution of Z among the nondiseased, as in Fig. 1. The sensitiv-
ity and specificity corresponding to each possible cut point
(calculated based on the normality assumptions) are given
below the horizontal axis. The calculations are based on a
sample size of 200 per group. It can be seen that in these
scenarios, the optimum cut point occurs in a place of high
specificity and moderate sensitivity.
The importance of high specificity in these scenarios is
tied to the fact that the probability of disease in each group
is relatively low. Given a low probability of disease and
imperfect specificity, the number of true positives might be
relatively low compared to the number of false positives.
This will lead to relatively greater bias and variance.
4. Choosing a cut point when the RR or OR
will be estimated using an approach that
adjusts for imperfect sensitivity and specificity
of the diagnostic test
Given data such as that in Table 1 and known values of
sensitivity and specificity, it is possible to estimate the RR
and OR using a method that adjusts for the imperfect sensitiv-
ity and specificity of the test [4,5]. The rationale for this
approach is as follows:
Let pT⫹|E and pT⫹|Ē stand for the probability of testing
positive in the exposed and unexposed, respectively, based
on a given cut point. There are two possible ways in which
a positive test result could occur: (1) the person really has
the disease and the test is correctly positive, and (2) the
person does not have the disease, but the test is incorrectly
positive. The probability of testing positive is the sum of
the probability of these two possibilities. Therefore,
pT⫹|E ⫽ ( pD|E)(sens) ⫹ (1⫺pD|E)(1⫺spec)
where “sens” and “spec” are short for the sensitivity and
specificity of the diagnostic test. Solving this equation for
pD|E results in:
pT⫹|E ⫺ (1⫺spec)
pD|E ⫽ .
sens ⫺ (1⫺spec)
Therefore, an unbiased estimate of pD|E is:
Total
nE p̂T⫹|E ⫺ (1⫺spec)
nĒ p̂D|E ⫽ .
sens ⫺ (1⫺spec)
 L.S. Magder, A.D. Fix / Journal of Clinical Epidemiology 56 (2003) 956–962 959

Fig. 2. Asymptotic mean squared error of the log RRstandard (plots a and b), and log ORstandard (plots c and d) at a range of cut points, under various scenarios.
All plots assume 200 subjects per group. Plots (a) and (c) are based on the assumption that the distributions of the quantitative assessment have the same
standard deviation, but differ in their means by two standard deviations. Plots (b) and (d) assume they differ by three standard deviations. The probability
of disease in the unexposed was assumed to equal 0.1 (thick), or 0.3 (thin). The probability of disease in the exposed was set so that the RR ⫽ 2 (plots a
and b) or the OR ⫽ 2 (plots c and d). The numbers for the cut points on the horizontal axes refer to distances from the mean in the undiseased.

Using the same approach to derive pD|Ē results in the
following adjusted estimates for the RR and OR:
p̂D|E p̂T⫹|E ⫺ (1⫺spec)
RR̂adjusted ⫽ ⫽ of the RR is asymptotically unbiased.
p̂D|Ē p̂T⫹|Ē ⫺ (1⫺spec)
and
p̂D|E/(1⫺p̂D|E)
OR̂adjusted ⫽
p̂D|Ē/(1⫺p̂D|Ē)
p̂T⫹|E ⫺ (1⫺spec) p̂T⫹ |Ē ⫺ (1⫺spec)
⫽ ÷ . values of pD|E and pD|Ē and sample size, a cut point can be
sens ⫺ p̂T⫹|E sens ⫺ p̂T⫹|Ē
For some data sets, these formulae can result in negative
values for the estimate. In those cases, the parameter should
be estimated with 0 or infinity depending on the situation.
For example, if the denominator of the adjusted RR estimate,
p̂T⫹|Ē ⫺ (1⫺spec), is less than 0, then there are fewer sub-
jects testing positive than would be expected if all the unex-
posed subjects were truly nondiseased. In this case, the data
are most consistent with no probability of disease in the
unexposed, and the appropriate estimate of the RR is infinity.
Note that, if the specificity is 1.0, the adjusted estimate
of the RR is equivalent to the standard estimate. This reflects
the fact that when specificity is perfect, the standard estimate
The asymptotic variances of these estimates are given by
equations (7) and (8) in the appendix. These variances
depend on the sensitivity and specificity of the test, the
values of pD|E and pD|Ē and the sample size in each group.
Again, the validity of these formulae does not depend on
assumptions about the normality Z. Therefore, for given
chosen which results in the lowest variance. Because
these estimates are asymptotically unbiased, their asymptotic
MSE is equivalent to their asymptotic variances.
Fig. 3a–d shows the asymptotic MSE of the adjusted
estimates calculated at a range of cut points under the same
scenarios used for Fig. 2. Again, it can be seen that the optimal
cut points occur for high values of specificity. Interestingly,
despite the fact that these estimates are unbiased, the MSE
of the adjusted estimate exceeds the MSE of the standard
estimate for many cut points.
960 L.S. Magder, A.D. Fix / Journal of Clinical Epidemiology 56 (2003) 956–962

Fig. 3. Asymptotic mean squared error of the log RRadj (plots a and b), and log ORadj (plots c and d) at a range of cut points, under various scenarios. All
plots assume 200 subjects per group. Plots (a) and (c) are based on the assumption that the distributions of the quantitative assessment have the same
standard deviation, but differ in their means by two standard deviations. Plots (b) and (d) assume they differ by three standard deviations. The probability
of disease in the unexposed was assumed to equal 0.1 (thick lines), or 0.3 (thin lines). The probability of disease in the exposed was set so that the RR ⫽ 2
(plots a and b) or the OR ⫽ 2 (plots c and d). The numbers for the cut points on the horizontal axes refer to distances from the mean in the undiseased.

5. Example 6. Further comments

As mentioned in the introduction, there is currently epide-
miologic interest in identifying risk factors for HSV8, a
recently discovered virus associated with Kaposi’s sar-
coma. Unfortunately, serologic assays to identify infection
are thought to have imperfect sensitivity and specificity.
Engels et al. [6] evaluated the sensitivity and specificity of
several assays at different cut points. Table 2 shows the
sensitivity and specificity at three optical density cut points
In practice, it will be impossible to determine the MSE
of the estimates at various cut points with certainty. For one
thing, there will generally be uncertainty regarding the
Table 2
Sensitivity and specificity of the K8.1 assay for detecting HSV8 at
various cut points, and the resulting mean square errors of risk ratio
estimates

for one of the enzyme-linked immunoassays designed to Optical density cut points
measure antibodies to the lytic phase glycoprotein K8.1. 0.80 1.00 1.50
Table 2 also shows the MSE of estimates of the risk ratio Sensitivitya 90% 85% 78%
under different scenarios, calculated using the formulae in Specificitya 83% 90% 98%
the appendices of this article. It can be seen that if the MSEb of log standard estimate of the risk ratio
standard estimate is used and the prevalence in the unex- Assuming prevalence in unexposed ⫽ 5% 0.33 0.26 0.16
Assuming prevalence in unexposed ⫽ 20% 0.114 0.072 0.038
posed is 5%, using a cut point of 1.5 leads to a far more precise MSEb of log adjusted estimate of the risk ratio
estimate than using a cut point of 0.8 (MSE ⫽ 0.16 compared Assuming prevalence in unexposed ⫽ 5% 0.79 0.55 0.26
to MSE ⫽ 0.33). A similar advantage of the larger cut point Assuming prevalence in unexposed ⫽ 20% 0.065 0.055 0.042
is seen when the prevalence is 20% and when the adjusted a
From Engels et al. [5].
b
estimate is used. Assuming 200 patients per group and a true risk ratio of 2.0.
 L.S. Magder, A.D. Fix / Journal of Clinical Epidemiology 56 (2003) 956–962
sensitivity and specificity of the diagnostic test at various
cut points. For another thing, the formulae given in the
Appendix provide only approximate MSEs, the quality of
which depend on the sample size. However, decisions often
have to be made in the presence of uncertainty, and the
formulae and the graphs in this article can still provide guid-
ance in choosing cut points. It is clear, for example, that
for relatively rare outcomes, good precision in estimation
requires high specificity, but is somewhat robust to depar-
tures from high sensitivity. This would suggest that one
should choose relatively high cut points in this context.
Interestingly, we found that in certain settings, the MSE
of the standard estimates are lower than the MSE of the
adjusted estimates. This occurs because the standard esti-
mates are biased towards 1.0, reducing the probability of
getting extremely large or small estimates. In fact, it can be
shown that the variances of the standard estimates are always
lower than the variances of the adjusted estimates. Thus, for
small sample sizes (where the MSE is predominantly de-
termined by the variance), the MSE will be lower for
the standard estimates than for the adjusted estimates.
However, the lower MSE of the standard method does
not mean that it is preferable to the adjusted estimates in
these settings. It can be argued based on the likelihood
principle [7] that if the sensitivity and specificity are known,
then the adjusted estimate of association is a more accurate
representation of the information in the data with respect to
the true value of the association. For example, consider a
data set in which the observed number of positive tests in
the exposed group is less than would be expected even if the
true disease risk in the exposed was 0, given the imperfect
specificity of the test. With such data it is arguable that the
data are most consistent with a RR of 0. This is what
the adjusted estimate would be, whereas the standard esti-
mate would not equal 0. Thus, if the goal of the analysis is
to report what the data say regarding the value of the associa-
tion, it is best to use the adjusted estimate.
There is a third approach to estimating RRs and ORs in
this context that obviates the need to choose a specific cut
point. In brief, using methods described in Magder and
Hughes [5], the exact value of Z can be used in risk assess-
ment using a probabilistic approach. Thus for example, those
with a very high value of Z might be classified as having a
higher probability of disease than those with a borderline
value of Z. These probabilities can be incorporated into an
algorithm to compute maximum likelihood estimates of risk
ratios or odds ratios. To use this approach the sensitivity
and specificity of the assay must be known (or assumed)
for multiple cut points.
Many studies seek estimates of the association of expo-
sure and disease, while controlling for potential confounders.
The adjusted method described above can be extended to
this context. A SAS macro is available on the Internet that
extends logistic regression to adjust for imperfect sensitivity
and specificity of a diagnostic test [8].
961
The methods described in this article are meant to be
used when disease status is a true dichotomy (e.g., infected/
uninfected). This should be distinguished from the situation
when disease status is matter of degree, and Z is a measure
of the degree of disease (e.g., when the disease is obesity
and Z is body-mass index). In the latter case, the use of a
cut point is mainly for the purpose of providing simpler
summaries of the data, and the notions of sensitivity and
specificity do not apply. Considerations for choosing a cut
point in that setting are discussed by Ragland [9].
The methods described in this article make the implicit
assumption that the sensitivity and specificity of the diagnos-
tic test are the same in both study groups. Although generally
reasonable, this assumption can be relaxed by using different
values for sensitivity and specificity in the terms in the
formulae relate to each study group.
Acknowledgments
This work was supported by research grant R0-1 AR
43727 of the National Institutes of Health.
Appendix
Formulae for the bias and variance of the standard estimates
based on a given cutpoint.
Let pD|E and pD|Ē stand for the probability of disease in
the exposed and unexposed respectively. Similarly, let pT+|E
and pT⫹|Ē stand for the probability of testing positive in the
exposed and unexposed respectively based on a given cut
point, T. Then,
pT⫹|E ⫽ PD|E sens ⫹ (1⫺pD|E)(1⫺spec) (1)
and
pT⫹|Ē ⫽ PD|Ē sens ⫹ (1⫺pD|Ē )(1⫺spec) (2)
where “sens” and “spec” refer to the sensitivity and specific-
ity of the diagnostic test based on the chosen cut point. The
standard estimate for the RR, p̂T⫹|E/p̂T⫹|Ē, is an unbiased
estimate of pT⫹|E/pT⫹|Ē. Therefore,
bias(logRR̂standard) ⫽ log
( ) pT⫹|E
pT⫹|Ē ( )
p
⫺ log D|E
pD|Ē
(3)
Expression (3) can be rewritten in terms of sens, spec,
pD|E and pD|E by substituting for pT⫹|E, and pT⫹|Ē based on
expressions (1) and (2).
Also, using the “delta” method [3],
(1⫺pT⫹|E) (1⫺pT⫹|Ē)
var(logRR̂standard) ≈ ⫹ (4)
nE pT⫹|E nE pT⫹|Ē
where nE and nĒ are the number of study subjects in the exposed
and unexposed groups respectively. Again, expression
962 L.S. Magder, A.D. Fix / Journal of Clinical Epidemiology 56 (2003) 956–962

(4) can be written in terms of sens, spec, pD|E and pD|Ē by var(logOR̂adj)
substituting from expressions (1) and (2).
( )
2
Using analogous reasoning, sens ⫹ spec⫺1 pT⫹|E(1⫺pT⫹|E)
⫽
(pT ⫹ |E ⫹ spec ⫺ 1)(sens ⫺ pT⫹|E) nE

( )
p /(1⫺pT⫹|E) (8)
bias(logOR̂standard) ⫽ log T⫹|E (5)
pT⫹|Ē/(1⫺pT⫹|Ē)

( )
2
sens ⫹ spec ⫺ 1 pT⫹|Ē(1 ⫺ pT⫹|Ē)

( )
pD|E/(1⫺pD|E) ⫹
⫺ log (pT⫹|Ē ⫹ spec⫺1)(sens ⫺ pT⫹|Ē) nĒ
pD|Ē/(1⫺pD|Ē)

and

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