Sensor Issues

Cite This: ACS Sens. XXXX, XXX, XXX-XXX pubs.acs.org/acssensors

Medical Sensors for the Diagnosis and Management of Disease: The

Physician Perspective
Bradford D. Pendley* and Erno Lindner
Department of Biomedical Engineering, 330 Engineering Technology, University of Memphis, Memphis, Tennessee 38152, United
States

ABSTRACT: The objective of this paper is to assist developers

of medical sensors to better formulate the clinically relevant
design criteria and required performance characteristics of their
novel sensor based on an understanding of how these devices will
be used by physicians. Sensor technologies play a central role in
medicine, and the most critical aspect of the sensor’s clinical
utility relates to these design decisions. Clinically, sensors are
used by health care providers to make both diagnostic and
management decisions, and the sensors that aid in these
decisions are evaluated by certain clinical, as well as analytical,
criteria. Failure to adequately address these end-user require-
ments can lead to the development of sensors without clinical
utility.
KEYWORDS: medical sensors, clinical, diagnostic, management, design

■ THE NATURE OF CLINICAL DECISIONS AND HOW

THEY ARE GUIDED BY TEST RESULTS
Like scientists and engineers, physicians are problem solvers.
The problems we address relate to a patient’s health and, in this
regard, physicians view problems in one of two categories:
diagnostic and management.
The diagnosis of a disease in a patient is the labeling of the
patient’s symptoms, physical exam findings, and test results
with the name of an established disease. For example, a person
who for 2 days has had a cough productive of sputum, fever of
101 °F (38.3 °F), an elevated white blood cell count in a
peripheral blood sample, and an opacity in the left lower lobe of
her lung on a chest X-ray could be given a diagnosis of
pneumonia. If the diagnosis is correct, it allows the physician to
predict and anticipate what might happen next based on an
understanding of the natural history of the disease process. For
example, if a patient has pneumonia, the prognosis is very
different than if the patient’s cough was due to post nasal drip.
A diagnosis is a working hypothesis of the most probable disease
based upon the available evidence. To arrive at a diagnosis, the
physician will group a patient’s pertinent symptoms with more
objective physical findings and test results. These “data” are
weighted based on their reliability and their predictive value for
that disease. Because a diagnosis is a hypothesis, physicians
actually construct a list, called a differential diagnosis, of several
diseases that could be explained by the “data” and then rank
them from most to least likely. The most likely disease is then
the diagnosis.
Once a diagnosis is made, the natural history of the disease is
known and this allows for predictions to be made as to what
may occur. Management decisions are those made by a
physician to mitigate the risk of the anticipated future adverse
effects of the disease. These decisions are guided by the results
of clinical studies that have tested various treatments or
interventions to alter the natural progression of the disease. For
example, a diagnosis of pneumonia imparts a risk of death to
the patient. However, with appropriate treatment and care, the
management of a patient with pneumonia can reduce the
chance of death and lead to the patient’s full recovery from the
disease. During the disease progression, a physician may also
collect additional information from the patient, physical exam
findings, and ongoing test results to aid in the ongoing
treatment. The decisions as to the specific treatment and care
are all management decisions.
Both diagnostic and management decisions are guided by
data provided by the patient, physical exam findings, as well as
the results of tests. For the purposes of this article, it is assumed
that a sensor designed to measure some analyte of interest,
which is linked in some pathophysiological manner to the
disease, provides the test results. For example, the ampero-
metric measurement of blood glucose in whole blood is a test
that can be used for both diagnosis and management of
diabetes mellitus, a disease in which the body’s ability to
regulate blood glucose is impaired. Thus, chemical sensor
technologies can play a central role in medicine.
For those of us involved in the design of sensor technologies
used in medicine, a few important ideas are central. First, one
must understand the analytical requirements for the sensor
Received: September 1, 2017
Accepted: October 30, 2017

© XXXX American Chemical Society A DOI: 10.1021/acssensors.7b00642

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(analyte, analytical selectivity, dynamic range, etc.) based upon
its intended use (e.g., as a sensor used in the diagnosis or
management of a disease). Second, and perhaps more critical, is
to understand when and how the sensor is used by the
physician: A test result is useful only when there is a question as
to how a physician should proceed (with a diagnostic or
management decision) and the result of the test will increase
the likelihood of making a good clinical decision. The
subsequent discussion will focus on these two ideas.
■
ASSESSING THE UTILITY OF A DIAGNOSTIC TEST
FROM THE END-USER (PHYSICIAN) PERSPECTIVE
One way physicians assess the diagnostic value of a test is using
the test’s positive and negative predictive values, both of which
are related to the sensor’s medical sensitivity and specificity. It
is important to note, in contrast to analytical sensitivity and
specificity, which informs about a sensor’s performance under
well-defined conditions, the medical sensitivity and specificity
measures the performance of a sensor for the diagnosis of a
disease and depends not only on the sensor’s performance
characteristics, but also the prevalence (i.e., how common the
disease occurs) of the disease.1,2 The values of a sensor’s
medical sensitivity and specificity are experimentally deter-
mined using the sensor’s ability to accurately assess whether a
patient is with or without a disease. The positive and negative
predictive values can be calculated as shown in Table 1 and
using eqs 1−4.
Table 1. 2 × 2 Table for the Evaluation of a Diagnostic
Sensora
disease present disease absent
test result positive true positive false positive
test result negative false negative true negative
a hypothetical sensor would be highly useful to help diagnose
The interpretation of each result (i.e., true or false positive or
negative) is influenced by selection of specific sensor cutoff value for
this binary choice. These cutoffs are selected based on receiver-
operator curves for the sensor which optimize the medical sensitivity
and specificity.3
true positive results
medical sensitivity =
true positive + false negative results
true negative results
medical specificity =
true negative + false positive results
true positive results
positive predictive value =
total positive test results
true negative results
negative predictive value =
total negative test results
From a sensor design viewpoint, the sensor detects an
analyte that ideally is uniquely related to the disease of interest
(i.e., the analyte is only present when the disease is present)
and therefore the sensor’s analytical sensitivity and selectivity are
related to the ability of the sensor to detect the disease. In
contrast, the sensor’s medical sensitivity and specif icity are related
to both the sensor’s ability to detect the analyte in addition to
Sensor Issues
the degree to which it is present in those individuals with and
without the disease. This is a critical point; the utility of a
sensor is not only determined by its analytical characteristics
but also by how prevalent the disease is (i.e., the occurrence of
the disease in humans). To illustrate this point, consider a
hypothetical sensor for influenza A (i.e., flu virus) with a
medical sensitivity of 95% and a medical specificity of 98%.
During the peak flu season, the prevalence of influenza among
people with “flu-like” symptoms (e.g., cough, fever, body aches,
etc.) might be 40%. So, if you consider 100,000 people with
these symptoms, 40,000 will have influenza while 60,000 will
not. Table 2 then shows the 2 × 2 table that can be constructed.
Table 2. 2 × 2 Table for the Evaluation of a Hypothetical
Influenza Sensor during Peak Flu Seasona
disease present disease absent
test result positive 38000 1200
test result negative 2000 58800
a
Values in the table are calculated as follows: Test result positive with
disease = sensitivity × 40,000; Test result negative with disease =
40,000 − test result positive with disease; test result negative without
disease = specificity × 60,000; test result positive without disease =
60,000 − test result negative without disease.
Therefore, if a patient with flu-like symptoms seeks medical
attention during the peak of flu season, there is a 40%
likelihood the patient has influenza. However, if the physician
orders an influenza test and the result is positive, the positive
predictive value of the result is 96.9% that the patient has
influenza (using eq 3 and Table 2). Therefore, the use of this
test is warranted because a positive result will mean the
physician is much more likely to assign a diagnosis of influenza
given a positive test results. Furthermore, the negative
predictive value is 96.7%, which would argue against the
diagnosis of influenza should the result be negative. Thus, this
influenza in this clinical situation.
Now consider a patient with flu-like symptoms who seeks
medical attention but not during flu season and when the
prevalence of influenza is 0.1%. If you consider 100,000 people
with these “flu-like” symptoms, only 100 will have influenza,-
while 99,900 will not. Table 3 then shows the 2 × 2 table that
can be constructed.
(1) Table 3. 2 × 2 Table for Evaluation of a Hypothetical
Influenza Sensor off Flu Season
disease present disease absent
(2) test result positive 95 1998
test result negative 5 97902
(3)
Now, if a patient with “flu-like” symptoms seeks medical
attention during a time with a low prevalence of flu, there is a
0.1% likelihood the patient has influenza. However, if the
(4)
physician orders an influenza test and the result is positive, the
positive predictive value of the result is 4.5% that the patient
has influenza. Therefore, the use of this test adds little to the
clinical picture as it is unlikely the person has influenza. Thus,
the same sensor used in this clinical scenario is not very useful.
Understanding the preceding example is critical for those
who develop sensors as you can “look up” the prevalence of the
disease for which you wish to develop a sensor. Then, using
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your estimate of the best medical sensitivity and specificity you
could reasonably expect (and understanding 100% is not an
option), you can decide a priori whether the sensor is likely to
achieve its goal. Because of this, diagnostic sensors made for
very low prevalence diseases (e.g, ovarian cancer) will likely not
have clinical utility and the Food and Drug Administration as
well as the U.S. Preventive Services Task Force have argued
against their usage.4,5
One pitfall of the “Baysean” or probabilistic approach to the
practice of medicine involves the changing prevalence of an
infectious disease during an outbreak of that disease. Many
times, patients will come to medical attention with non-disease-
specific symptoms such as fever which can have multiple
etiologies. Early on in what will become an epidemic, the source
of fever is misidentified because the prevalence of that disease is
thought to be low. For example, leptospirosis is an infectious
zoonosis disease with a prevalence (in tropical regions) of 10
per 100,000 people.6 However, if there were an outbreak, the
prevalence would climb higher. If one uses the “normal” (i.e.,
not during an epidemic) prevalence, there is limited utility in
designing a sensor to be used to screen people for leptospirosis
because to achieve a respectable positive predictive value of
91%, the medical sensitivity and medical specificity needed for
such a sensor is 99.999%, a tall order. However, in times of
outbreak when the prevalence increases, such a sensor may
have clinical utility.
■
ASSESSING THE UTILITY OF A MANAGEMENT
TEST FROM THE END-USER (PHYSICIAN)
PERSPECTIVE
Ultimately, the value of a management test is in its prognostic
value, that is, the ability of the test result to influence the
medical decision related to the ongoing care of a patient. For a
sensor to be useful to a physician in making management
decisions, two criteria must be met: (1) The presence of or
variation in the analyte’s concentration must be linked to the
disease’s progression, and (2) the sensor must be able to
measure the analyte concentration accurately within the matrix
of interest (e.g., blood, tears, urine, tissue, breath, etc.) within a
task specific time frame.
Many of us who design sensors are intimately familiar with
the second criterion. Considerable efforts are expended to
create a sensor that can selectively measure the analyte within a
complex matrix and in a specified time frame. However, for a
medical decision based on a test result there are important
related issues. For example, if the expectation is that the sensor
provides insight into whether a disease is local or widespread
(e.g., cancer), it requires attention be paid to sampling.
Consider the case of the deadly skin cancer melanoma. If the
disease is localized to the skin, the 5-year survival rate is about
97% while the survival rate for widespread, “metastatic”
melanoma is 15−20%.7 Therefore, efforts to detect melanoma
cell free circulating DNA, the so-called “liquid biopsy”, provides
an opportunity for such a sensor to provide information crucial
to the management of this disease by providing information on
its extent of spread.8 However, such free circulating melanoma
DNA are not necessarily homogeneously distributed in the
bloodstream, and its detection is limited by the sampling error.
One implication of the second criterion is often overlooked
by those of us who design sensors because we are focused on
the sensor and not on its use. The concentration range of a
sensor for a physician and its accuracy are critical performance
characteristics only in the range of concentrations of the analyte
C DOI: 10.1021/acssensors.7b00642
Sensor Issues
that helps with management decisions. For example, consider a
blood glucose sensor. Physiologically, blood glucose in a person
without diabetes mellitus is tightly regulated within a range of
approximately 70−140 mg/dL (range from fasting to after
eating). For those people with diabetes mellitus, blood glucose
can increase substantially, even into the 2000 mg/dL range or
more. On the other hand, if the patient is taking medicine that
can lower blood glucose, it can be as low as 10−20 mg/dL
before death.
A brilliant solution that allowed for the combination of
clinical requirements with analytical performance for blood
glucose measurements was borne out of the Diabetes Control
and Complications Trial9 in which clinicians studied the effects
of tightly regulating blood glucose in patients with Type 1
diabetes mellitus. In this trial, tight blood glucose control with
insulin led to increased risk of hypoglycemia and its life-
threatening consequences; it also led to fewer long-term
medical complications with better blood glucose control. This
meant that controlling a patient’s blood glucose as close to the
physiological range led to fewer long-term complications of
diabetes. However, such “tight” control also increased the risk
of hypoglycemia so the accurate measurement of blood glucose
in certain ranges became critical. The Parkes error grid was
developed after surveying 100 physicians who treat patients
with diabetes mellitus and whose “expert consensus” allowed
Parkes and co-workers10 to construct a scatter plot of blood
glucose readings (test device vs standard device) partitioned
into 5 regions (A−E) where the analytical requirements of
accuracy were set by the clinical requirements. An updated
version of this is currently under development.11 The concept
of medical “expert consensus” driving analytical performance
characteristics is precisely what we advocate.
A consequence of the Parkes error grid is that, as long as the
detection limit of a sensor is adequate to detect the lowest level
of analyte needed for a clinical decision with minimal
uncertainty, there is no need to optimize the detection limit.
In fact, doing so might sacrifice other sensor performance
characteristics that do impact a sensor’s clinical utility. On the
other hand, it is important to recognize that a theoretically
attainable (often the published) detection limits may not be
manageable in real patient samples because they might have
been calculated from the following: (i) results recorded in
standard solutions without any potential interfering compounds
or (ii) the standard deviation of a background signal (sB)
instead of the residual mean standard deviation of the data
points (RMSD) around the calibration curve with a slope of S
within the physiologically relevant concentration range (c1DL = 3
× sB/S vs c2DL = 3 × RMSD/S, respectively). If c1DL is termed
detection limit, c2DL is the resolution of the method, i.e., the
smallest concentration difference which can be determined with
the sensor.
Unfortunately, papers on novel sensors often report
detection limit values without justification of the method and
calculation used for their determination.
With respect for a sensor’s utility for diagnosis or
management, the agreement between the results provided by
an established method/sensor and the new method/sensor is
probably the most important. The level of agreement is most
commonly determined in head-to-head comparison of a new
method/sensor with an established method/sensor. While
experimentally method comparison studies are straightforward,
the statistical analysis can be quite complicated, and a careful,
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methodical approach is needed to minimize the possibility of
misinterpretations of the results.12
Most of us who work on the design and characterization of
medical sensors do not pay adequate attention to the largest
challenge for management sensors, namely, that most analytes
detected with management sensors are actually surrogate
markers for that disease and its progression. A surrogate
marker is something that is measured (e.g., a molecule or ion)
whose presence or concentration is believed to be related to the
disease progression or status. Such a surrogate marker is used
when no analyte directly related to the disease is available or is
measurable with existing methods, and the surrogate has been
shown through clinical trials to be linked to the disease. For
example, many commercial point-of-care testing devices
measure serum creatinine levels electrochemically or optically
and the resultant value is used as an indicator of renal (kidney)
function.13 Creatinine is a metabolite of protein catabolism that
is normally released into the blood and filtered by the kidneys
at a constant rate. The rate of filtration through the kidneys
(called the glomerular filtration rate, GFR) is used clinically to
assess the functioning of the kidneys; thus, serum creatinine
level is a surrogate marker for renal function. However, the
utility of creatinine as a surrogate marker for GFR has
limitations. For example, if a person eats a protein rich meal,
exercises vigorously, or takes creatinine supplements, the
assumption that creatinine is being released into the blood at
a constant rate is incorrect; serum creatinine will rise in this
circumstance and the calculated GFR will be lower. Thus, renal
function “appears” to be less because the assumptions for the
use of creatinine as a surrogate marker are not valid in these
circumstances. Fortunately, in this case, clinicians understand
these potential errors and can identify them when present.
■
CONCLUSION
Both diagnostic and management decisions can be greatly
enhanced with information from sensors, but developers should
understand the clinical criteria by which such sensors will be
judged and used and their associated pitfalls. The development
of medical sensor technologies to aid health care workers in
making decisions should focus on the clinical requirements and
the information content the sensors will provide. It is essential
to understand that even the best sensors, with outstanding
analytical characteristics, will most likely not have clinical utility
for the diagnosis of very low prevalence diseases. On the other
hand, the same sensors in another environment or other times
with high prevalence of the disease could be extremely useful.
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: bpendley@memphis.edu.
ORCID
Bradford D. Pendley: 0000-0002-3379-8376
Erno Lindner: 0000-0002-2561-4784
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors gratefully acknowledge the financial support from
the FedEx Institute of Technology through the Sensor Institute
of the University of Memphis (Sensorium).
D DOI: 10.1021/acssensors.7b00642
Sensor Issues
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