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Gari D. Clifford and David Clifton

Institute of Biomedical Engineering, Department of Engineering Science, University of
Oxford, Oxford OX3 7DQ, United Kingdom; email: gari@robots.ox.ac.uk,
davidc@robots.ox.ac.uk

Annu. Rev. Med. 2012. 63:479–92 Keywords

First published online as a Review in Advance on
November 4, 2011
The Annual Review of Medicine is online at
med.annualreviews.org
This article’s doi:
10.1146/annurev-med-051210-114650
Copyright  c 2012 by Annual Reviews.
All rights reserved
0066-4219/12/0218-0479$20.00
electronic medical record, eHealth, eICU, mHealth, telemedicine,
telehealth
Abstract
Healthcare information, and to some extent patient management, is
progressing toward a wireless digital future. This change is driven partly
by a desire to improve the current state of medicine using new technolo-
gies, partly by supply-and-demand economics, and partly by the utility
of wireless devices. Wired technology can be cumbersome for patient
monitoring and can restrict the behavior of the monitored patients, in-
troducing bias or artifacts. However, wireless technologies, while mit-
igating some of these issues, have introduced new problems such as
data dropout and “information overload” for the clinical team. This
review provides an overview of current wireless technology used for
patient monitoring and disease management. We identify some of the
major related issues and describe some existing and possible solutions.
In particular, we discuss the rapidly evolving fields of telemedicine and
mHealth in the context of increasingly resource-constrained healthcare
systems.

479
 ME63CH32-Clifford ARI 12 December 2011 14:21

INTRODUCTION resources are plentiful and there are few

barriers to direct monitoring. Moreover, there
Although it is difficult to pinpoint the begin-
may be advantages to tethered monitoring,
Telemedicine (also nings of wireless health monitoring, its prac-
telecare or if it means that care providers are obliged
tical roots might be traced back to the in-
telehealth): medical to interact with the patient more than they
vention of the battery by Volta in 1800, the
practices mediated otherwise would. One might also argue that
first wireless communication by Dolbear in
remotely, such as over continually disturbing the patient with alarms
the phone, by video, or 1882, and the first electrocardiogram (ECG)
generated by wireless monitoring systems may
asynchronously by Einthoven in 1906.1 Einthoven initiated the
through a web service be detrimental to the patient’s health (2, 3).
field of telemedicine by directly connecting an
An important reason for the introduction of
ECG: ECG-measurement device, the galvanometer,
electrocardiogram telemedicine is the increasing need to reduce
to telephone lines and thereby transmitting the
costs. A recent report from the GSM Associ-
mHealth: mobile ECG from his laboratory to a nearby hospi-
healthcare, generally ation and McKinsey (4) warns that, if exist-
tal (1). Although only a recent development (in
referring to ing trends in expenditure continue, spending
any practical sense), wireless energy delivery is
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telemedicine using a on healthcare will consume an unsustainable

now also becoming a reality. Practical wired en-
mobile phone proportion of the wealth of developed nations
ergy delivery is still mainly confined to battery
(up to 25% of gross domestic product in the
technology, which is a form of noncontinuous
United States, for example), with chronic ill-
semitethered “sneaker-net”-like energy trans-
ness management accounting for 80% of the
fer.2 With these developments, wireless health
growth in costs. For example, 210 million peo-
monitoring became possible.
ple worldwide suffer from chronic obstructive
Wireless medical data transmission has also
pulmonary disease (COPD) (5), which will be-
been driven by a desire to provide remote analy-
come the third-largest cause of death within ten
sis of physiological data, assuming that resource
years. Even if smoking ceased today, the effect
allocation can be more effective in such a man-
on COPD statistics would not be seen for up
ner. It seems intuitively obvious that it is advan-
to 20 years (6). COPD is the second most com-
tageous to review medical data in this manner
mon cause of emergency hospital admissions,
in sparsely populated regions or in environ-
with one in eight acute emergency admissions
ments where installing and maintaining wiring
being the result of an acute COPD exacerba-
is difficult (such as in quarantined regions,
tion. COPD is also the fifth-largest cause of
across borders, in hazardous locations, or in ex-
readmission; 30% of the COPD patients hos-
tremely remote regions). However, it is unclear
pitalized in the United Kingdom in one year for
whether wireless transmission of medical data
treatment of acute exacerbations are readmitted
confers advantages in high-density monitoring
at least once within the following 12 months.
environments where healthcare knowledge and
As a result, COPD accounts for the second-
highest number of total occupied-bed-days in
1
Clearly Einthoven and Dolbear relied heavily on the works the United Kingdom’s National Health Ser-
of Maxwell and other engineers, physicists, and mathemati- vice. There is evidence that chronic diseases
cians who provided the theories and devices on which they of physical origin also have a large impact on
built their ideas and inventions. We identify these points as
key moments in the scientific evolution of wireless devices, mental health. Along with diabetes, cardiovas-
noting that such ideas rarely occur in isolation and that in- cular disease, and respiratory-related diseases,
dependent codiscovery is less rare than one would imagine, mental health problems will present the largest
as the case of Dolbear shows us.
2
challenges to global healthcare, in both
“Sneaker-net” is a colloquialism describing the delivery of
information by the physical transportation of static media resource-rich and resource-poor settings, over
such as a hard disk-drive. It is still a truism today that the the coming decades (5).
fastest rate of data transfer to most locations is achieved by There is some hope that mHealth may pro-
physically copying data to a selection of hard disk-drives and
driving them at high speed to their destination. Batteries are vide a way to manage such illnesses and pro-
therefore the energy analog of a “sneaker-net.” vide a low-cost way of dealing with related

480 Clifford · Clifton

 ME63CH32-Clifford ARI 12 December 2011 14:21
issues such as compliance (4). There is prelim-
inary evidence that telemedicine solutions may
be able to reduce the rate of emergency ad-
missions, but this has only been demonstrated
in the United Kingdom in studies compris-
ing small numbers of patients. The best results
have been reported by the Veterans Adminis-
tration (VA) in the United States, which showed
a 20.7% decrease in health service utilization
by a cohort of 1,963 patients; however, this was
achieved at a relatively high cost of $1,600 per
patient per year (7). The latest systematic re-
view of home telemedicine for COPD showed
that existing telemedicine solutions reduce the
Annu. Rev. Med. 2012.63:479-492. Downloaded from www.annualreviews.org
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rate of hospitalization, but patients with tele-
phone support had a higher mortality rate
than those in the group that received standard
care (8).
There are around 60 telemedicine projects
currently running across the United Kingdom’s
National Health Service in England alone.
Some have demonstrated positive outcomes,
although most of these have been small-scale
proof-of-concept studies with typically fewer
than 100 patients enrolled. There is also con-
siderable variation in the magnitude of the
outcomes reported (9).
The case for wireless technology seems far
more pressing in resource-constrained loca-
tions, such as the rural and peri-urban envi-
ronments of developing countries. Over the
past decade there has been a “leapfrogging” of
wired communication systems in such places,
where mobile phone technology provides low-
cost and affordable communication for almost
all of society. Recent estimates indicate that up
to 90% of the world’s people are within reach of
a mobile phone transmitter, and that the num-
ber of mobile phone users is approaching the
number of literate people on earth (10). More-
over, the lack of trained healthcare specialists in
developing countries, and the migration of such
personnel to higher-paying economies, means
that there is a pressing need for mHealth, if
a financially affordable delivery model can be
implemented. In fact, mHealth is beginning to
be adopted rapidly throughout both developed
and resource-poor economies.
Before discussing this new area of wireless
monitoring, we first present an overview of the
types of data transmitted and discuss some of
BP: blood pressure
the related issues concerning privacy, standards,
BR: breathing rate
and evaluation. In particular, we concentrate on
ambulatory monitoring of patients in the home SpO2 : peripheral
oxygen saturation
(or “biomonitoring”), telemedicine, and recent
trends in hospital implementations of wireless
monitoring. We also discuss evidence (or lack
thereof ) concerning the success of such moni-
toring systems.
BIOMONITORING
A comprehensive review of physiological data
measured by biomonitoring is provided by
Budinger (11), who describes the various meth-
ods with which each parameter has been ac-
quired to date, and the wireless standards by
which they are transmitted (and which are still
used in contemporary practice). The author
concludes that blood pressure (BP), breathing
rate (BR), the ECG, and peripheral oxygen
saturation (SpO2 ) are parameters that require
“more or less continuous monitoring” in the
home, noting that engineering design contin-
ues to be limited by the battery life of the equip-
ment. Other parameters that are typically mon-
itored wirelessly include blood glucose, weight,
physical activity, and sleep.
In the hospital environment, wireless
telemetry has been mostly confined to ECG;
(noninvasive) BP and SpO2 have also been mon-
itored in a similar fashion. The main reason
for in-hospital telemetry is to grant the patient
some freedom of movement (enabling a quicker
recovery) and yet allow continuous monitor-
ing for life-threatening events, such as arrhyth-
mias. Typically, a radio-frequency system, such
as the hospital’s Wi-Fi network, is used to trans-
mit the data. Recently, several companies have
made telemetry systems available in the inten-
sive care unit (ICU). These “eICU” systems
vary in functionality but are based on transmis-
sion of the standard bedside vital signs (such as
the ECG) and on integrating them with other
hospital information for display on a remote
“dashboard,” allowing the clinician to interact
www.annualreviews.org • Wireless Technology in Medicine 481
 ME63CH32-Clifford
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ARI 12 December 2011 14:21
remotely with the bedside caregivers. A webcam
is therefore often also employed. The integra-
tion of so much real-time data has facilitated the
use of computational predictive alert systems,
which have shown some promise, particularly
in the lower-acuity setting (12).
Several systems for nonhospital wireless
health monitoring have been implemented.
Alaoui et al. (13) described the monitoring of
congestive heart failure, which affects five mil-
lion Americans. In congestive heart failure, the
heart becomes weak and loses its ability to pump
blood throughout the body, resulting in the ac-
cumulation of fluid in the lungs. Daily monitor-
ing of weight, BP, and SpO2 is required. The
authors describe a secure Internet-based system
for transferral of patient data from a home mon-
itoring measurement device to a central station
used by clinical staff.
Donoghue et al. (14) described the archi-
tecture of a telemedicine system that noninva-
sively measures BP every 30 min, using mo-
bile phones as a medium between Bluetooth
sensors and the central station. Roine et al.
(15) surveyed the literature for publications on
“telemedicine” between 1990 and 2000. Fifty
studies were deemed suitable for consideration,
of which 34 assessed clinical outcomes and 16
assessed economic benefit. The authors found
that “most of the available literature referred
only to pilot projects. . .and most of the stud-
ies were of low quality,” part of the so-called
“plague of pilots.” These studies included tele-
radiology, in which CT scans are transmitted
remotely; those involving home monitoring re-
quired patient involvement in order to make
physiological measurements. The authors con-
cluded that economic benefits of telemedicine
have yet to be proved, agreeing with a criticism
previously made in a Lancet editorial (16).
Similarly, Celler et al. (17) noted that “as is
common for most telemedicine applications, a
strong evidence base for cost effectiveness and
improved healthcare outcomes is still not avail-
able,” which they attributed to the lack of con-
trolled trials described in the literature. In a re-
view of 175 articles on telemedicine in chronic
disease management, these authors found
482 Clifford · Clifton
only four that considered cost-effectiveness.
Whitten et al. (18) concluded from a study of
551 articles on telemedicine that “only 38 con-
tained any type of real data. Because many of
these 38 studies proved to be inadequately de-
signed or conducted, we were unable to per-
form a traditional meta-analysis.” Mair et al.
(19) found that only 29 of 246 studies that men-
tioned cost as an outcome were suitably rig-
orous for the purposes of meta-analysis. Agha
et al. (20) showed from a study of a one-year
telemedicine program in the United States that
telemedicine costs (involving teleconsultation,
with patients actively involved in vital-sign ac-
quisition) were 58% that of routine care (in-
volving outpatient consultations at a treatment
center), and 29% that of onsite care in the pa-
tient’s home by clinical staff.
mHEALTH
Although Internet-based systems are increas-
ingly common, a significant growth area is the
monitoring of health using a mobile phone.
Waves of low-cost or freely downloadable mo-
bile phone applications (“apps”) are beginning
to appear, which either process the data on
the mobile phone itself or process it remotely
after upload to a central server (in so-called
“cloud computing” environments). These apps
include stethoscopes, sleep structure analyzers,
exercise or physical activity assistants, cardiac
analysis systems, mental health trackers, and
Parkinson’s disease trackers, among many
others (21–23). Mobile phones are being con-
structed to be used with integrated health sen-
sors (24), to interact with external sensors (25),
to allow connection to plug-in external sensors
(26), or simply to exploit the relatively complex
suite of sensors that a typical mobile phone now
contains (such as a microphone, camera, GPS,
and accelerometer) to provide information on
a subject’s health.
However, it is not sufficient merely to col-
lect data. An integrated approach is needed,
whereby data are stored in a flexible database
and both humans and automated algorithms
can parse the data to provide warnings of
 ME63CH32-Clifford ARI 12 December 2011 14:21
deterioration and other actionable information.
Many such architectures have been created,
ranging from in-hospital wireless ECG mon-
itoring to complex mHealth systems. Celi et al.
(27) implemented an open-source telemedicine
infrastructure, primarily designed for use in de-
veloping countries, which allows upload of any
type of medical data to a remote server and syn-
chronization of that data set to an open-source
medical record system called OpenMRS (28).
The system also allows multiple independent
annotations of the data, feedback to the pa-
tient or healthcare worker, and annotation with
a universal medical lexicon (the UMLS).
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The provision of healthcare through using
mHealth has several natural advantages over ex-
isting care pathways:
1. Lower cost of capital investment
2. Users’ familiarity with devices and
interfaces
3. A generic interface that can be easily cus-
tomized for disadvantaged populations
(large icons, voice recognition)
4. Seamless data upload with accurate time-
stamps and geospatial markers
5. Natural security (led by “mBanking”)—
i.e., access requires something you know
(a password) and something you have (the
device)
6. Use of a private, yet individual, iden-
tifier, e.g., International Mobile Equip-
ment Identity (IMEI) number or Media
Access Control (MAC) address
7. Allows construction of a long-term medi-
cal record, allowing detailed personalized
healthcare
8. Automated data upload, no need for user
intervention
9. Natural route for data feedback to the
user
THE PROBLEMS OF WIRELESS
HEALTHCARE MONITORING
Wireless monitoring systems also allow us
to address a largely ignored problem in
medicine—the fact that we often sample be-
low the “Nyquist frequency,” leading to a
phenomenon known as aliasing, which intro-
duces “phantom” effects into the signal when
recording data less frequently than twice the
fastest change in the data. Nyquist’s sampling
theorem states that we need to sample at least
twice as fast as the highest frequency in the sig-
nal in order to obtain an accurate representa-
tion of the information that we are attempting
to obtain. A typical example of this is when a
wheel on a cart in an old western film picks up
speed and starts to rotate faster than 20 rev-
olutions per second. Because the film is being
shot at 40 Hz (or frames per second), the wheel
starts to appear to spin in reverse. (We can guess
that the wheel shouldn’t be spinning in that di-
rection, and apply some extrapolation to fill in
the data and make the wheel appear to spin the
right way, but we can only do so because it is
a simple linear system and we are absolutely
sure that the wheel cannot spin backwards!
However, in general, we will never know if we
have filled in the missing data correctly.) Now
set this in the context of current recommenda-
tions for home monitoring of BP in the United
States by the American Society of Hyperten-
sion, which suggest we should record BP twice a
day (29). BP normally has at least two peaks and
two troughs during a 24-h period (30), so sam-
pling only twice in a 24-h period could acciden-
tally result in measurement of either the highest
or lowest excursions of the BP, falsely indicating
hypertension or hypotension. It is interesting to
note that previous recommendations suggested
sampling BP once per day, or less frequently,
which is known to have led to overprescrip-
tion of hypertensive medication due to “white
coat syndrome” (a temporary increase in a pa-
tient’s BP due to the stress of being examined
by a clinician). This syndrome may therefore
be sometimes compounded by aliasing. A re-
cent study by Hug et al. (31, 32) demonstrated
that hypotensive alarms generated as a result of
the monitoring of intra-arterial BP in the ICU
were systematically being rejected by clinicians
even when those alarms were correct, probably
because no immediate review procedure was in
place. On average, hypotensive events (which
have been linked to poorer outcomes in the
www.annualreviews.org • Wireless Technology in Medicine 483
 ME63CH32-Clifford ARI 12 December 2011 14:21
130
120
110
MBP (mmHg)
100
90
80
70
Annu. Rev. Med. 2012.63:479-492. Downloaded from www.annualreviews.org
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60
0 1 2 3 4 5 6
Time (h)
Figure 1
Undersampling mean blood pressure (MBP): continuous measurements ( gray
line) break a threshold set at 70 mmHg (red dashed line) between t = [1 2] h,
while manual measurements (black dots) undersample the blood pressure, and
fail to spot the episode of hypotension below 70 mmHg.
ICU) were missed for over 4 h. Figure 1 il-
lustrates this undersampling effect, in which a
sampling of the continuous arterial BP mea-
surement at infrequent intervals (black dots) can
fail to spot episodes of interest (in this case, an
episode of hypotension).
However, increasing the volume of data (and
collecting data outside of a medically supervised
environment) brings with it four new problems.
The first is that without automated analysis,
more clinical experts are required to inspect the
data. The second issue is that the data obtained
from mobile patients are generally noisier and
harder to interpret than data obtained from a
system in which the patient is not mobile, lead-
ing to higher false-alarm rates. The third issue
is that as the number of false alarms will in-
crease with increasing quantity of data acqui-
sition, there will be a corresponding increase
in follow-up tests and treatments. The fourth
issue is that as we start to sample more fre-
quently, we are likely to observe new patterns
in the data, with which clinical teams may not
be familiar and which they may find difficult to
interpret.
484 Clifford · Clifton
A possible solution to the increased volume
of work that arises with increasing data acqui-
sition is to increase the level of automation
in analysis of the data. Generally, the clinical
community has been slow to adopt automatic
analysis systems, but this may be because most
current monitoring systems are designed to
work on a single-channel basis (such as gen-
erating an alarm when a single physiological
quantity increases above some predefined
threshold). When data are fused from several
sources, more “intelligent” decisions can be
made by automated algorithms, which are more
robust in the presence of the uncertainty intro-
duced by movement artifact and sensor noise.
When the need for extreme sensitivity (to never
miss a serious event) is combined with the
single-channel nature of current monitoring,
we observe high rates of false alarms ranging
from 20%–95% depending on the alarm type
(33). Extreme sensitivity means that noise will
often trigger false alarms, which can result in
alerts being ignored in practice. One solution to
this problem is to develop signal-quality metrics
for each channel and fuse the data in a manner
that dynamically takes account of the underly-
ing trust that can be put in each signal (33–35).
In the hypotension study mentioned above
(32) and and associated works (31, 33), the
authors also showed that hypotensive events
could be detected in a timely manner (without
increasing the number of false alarms) by using
good signal-quality vetting algorithms and
automated BP analysis software. The use of
signal-quality analysis and automated decision
support will become more important as we
increase the volume of data and number of
patients that we routinely monitor. The clinical
task may become one of identifying unusual
cases or errors in the automated algorithms,
auditing the automation and taking over when
there are obvious failures. Of course, with in-
creasing complexity of monitoring, it becomes
harder for clinicians to assimilate scores of
parameters and reason in many dimensions
simultaneously.
A cardiorespiratory monitor produced for
the Collaborative Home Infant Monitoring
 ME63CH32-Clifford ARI 12 December 2011 14:21
Evaluation (CHIME) project measures respi-
ration from the impedance pneumogram, heart
rate (HR) and HR variability from an ECG,
SpO2 from a pulse oximeter, and sleep position
from an accelerometer (36). In a clinical study
of home infant monitoring, sensitivity to brady-
cardia was reported to be 100%, while positive
predictivity was 6.5%. The authors concluded
that although the system is sensitive to move-
ment artifact, the quality of acquired data (and
its breath-detection algorithm) makes it prefer-
able to conventional monitors.
Significant recent advances have been made
in noncontact wireless health monitoring.
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These include using cameras to monitor phys-
ical movement during sleep or to extract HR
and respiration rate using video data of a pa-
tient’s face acquired from webcams (37). Such
work has shown promising noncontact mea-
surement of the ECG, which can detect a coarse
heartbeat at a distance of several centimeters.
Radar has also been used to measure BR and
HR in low-power Zigbee-compliant devices
such as that proposed by Zito et al. (38) and
Scilingo et al. (39), which can be integrated into
the fabric of a shirt. Audio and video analy-
sis is also being used to identify sleep-related
diseases (21), Parkinson’s disease (22), and
depression (23).
DATA TRANSMISSION
AND INTERCHANGE
A survey of remote vital-sign monitoring by
Meystre (40) noted that “telemonitoring is still
overshadowed by teleconsulting and teledi-
agnosis.” Meystre used the term biotelemetry
to distinguish the remote measurement of
physiological data from other home-based care
systems. The author concluded that bioteleme-
try systems are typically developed in isolation,
and that an equivalent to the DICOM (Digital
Imaging and Communications in Medicine)
standard used by radiologists to transmit im-
ages is required. He suggested that this could be
based on Health Level 7 (HL7), which was in-
troduced in 1987 for electronic transmission of
healthcare data and is currently in its third ver-
sion. HL7 is based on XML (41) or on the Eu-
ropean VITAL standard (42), which specifies
formats for transferring vital-sign data. Lebak
et al. (43) proposed an HL7-based architecture
whereby vital-sign data were collected contin-
uously from sensors by a local server, which
periodically uploaded batches of patient data
to a remote central server, usable by clinicians.
There are several standards for wirelessly
transmitting data, including the battery-hungry
high-bandwidth Bluetooth, its low-powered
cousin Zigbee, the various forms of Wi-Fi,
standard mobile phone voice channels, Short
Message Service (SMS), Multimedia Messaging
Service (MMS), General Packet Radio Service
(GPRS), Universal Mobile Telecommuni-
cations System (UMTS), satellite, and even
standard radio. Each of these has trade-offs in
terms of cost, bandwidth, power consumption,
and reliability. Several of these communication
methods do not possess error-checking, so
data can be lost without the sender knowing.
Accurate time-stamping of data is a particularly
problematic issue in these circumstances. In
medicine, the accuracy of the time at which
an event occurred is often important; without
it causality can be lost, timely interventions
prevented, or erroneous patterns observed that
mask events or lead to false alarms. SMS (or
“texting”) is particularly sensitive to such issues.
Texts sometimes take >24 h to arrive at their
destinations, with no guarantee of preserving a
given sequence of messages. SMS is therefore
only appropriate for a very limited type of trans-
missions, which are relatively insensitive to
missing data and which change on the timescale
of weeks rather than days (such as transmissions
of a patient’s weight). Time-stamping issues can
be solved for systems that have a sampling fre-
quency on the order of a few seconds; the time
can be extracted from the mobile phone (which
is regularly synchronized with the mobile
network) and then appended to the transmis-
sion. GPRS and Wi-Fi connections also allow
solutions for timeliness and reliability through
additions to the communications protocol that
explicitly determine quality of transmission
(e.g., 27).
www.annualreviews.org • Wireless Technology in Medicine 485
 ME63CH32-Clifford
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ARI 12 December 2011 14:21
Storage is often a combination of binary
data (for data acquired at a high frequency,
such as ECG) and relational databases (which
often store lower-frequency data such as daily
weight, or data extracted or aggregated from
higher-frequency data). Several standards
exist for signals and images, such as the
European Data Format (EDF) and the Digital
Imaging and Communications in Medicine
(DICOM) standard, but no standard exists
for relational databases, although examples
have been made available with an open-source
license (44). Many monitors and systems now
exchange data via HL7, as described above.
However, HL7 only tells devices how to
communicate; it does not encode the semantics
of the contained data. For example, a typical
transmission could include data concerning a
BP measurement (stored as a number using
text), a binary ECG snippet, and a diagnosis.
The data packet does not specify from which
monitor the BP reading came, or whether it was
measured invasively or noninvasively, or even
from what location on the body the reading was
taken (which will change the reading and its
interpretation). The ECG may be represented
in an arbitrary format, and the diagnosis may
appear as free text in any language.
The issues surrounding data formats are rel-
atively trivial to solve if a sufficiently flexible and
open format is used such as the Wave Form
DataBase format (45). Incidentally, the XML
format specified by the U.S. Food and Drug
Administration (FDA) is probably not appro-
priate as a standard because it becomes rapidly
cumbersome for the transmission of even mod-
erate recording lengths of ECG data. The
issue of unknown sources of data can also be
solved easily. An example is the current picture
format taken by digital cameras and cameras
in mobile phones. Each picture carries meta-
information concerning the compression, fil-
ters, camera chassis, lens type, resolution, and
shutter speed used to take the photograph,
along with the time at which it was taken, and
the location (if GPS is enabled). To solve the is-
sue of unknown sources would require a change
in regulation to require manufacturers to send
486 Clifford · Clifton
meta-data in the HL7 packets that specify de-
vice configuration, details of any filters applied
to the data, and known accuracy. It is also im-
portant that signal-quality information is sent
with each transmission, since all data are cur-
rently treated equally, independent of the actual
reliability of the acquisition system used to ob-
tain a given measurement. Most devices have
built-in signal-quality evaluation, such as the
“movement artifact” in a typical pulse oxime-
ter, but it is extremely rare for devices to provide
anything more than a coarse version of the qual-
ity index on a visual display. In order to process
data accurately, it is important to understand
how much each measurement can be trusted.
It is almost impossible to differentiate artifacts
from real events if only derived parameters are
provided (for example, only a BR measurement
and not the impedance plethysmography sig-
nal used to derive it). When the quality of the
underlying signal is accurately estimated, it is
possible to use this information to greatly im-
prove the sensitivity and specificity of monitor-
ing algorithms that subsequently use the data
(34).
The issue of ontological encoding of data
is far more challenging to solve. Although sev-
eral ontologies exist (e.g., the Unified Medical
Language System and its constituent lexi-
cons such as SnoMed, LOINC, and RxNorm),
which enable a standardized description of
medical data, there is a problem of degener-
acy: a given medical condition or intervention
can be encoded in multiple ways, making the
comparison of medical data time-consuming or
impossible. Some progress has been made in
this arena by using limited use-specific subsets
of given ontologies (27, 44). Unfortunately, the
explosion of proprietary systems in the mobile
monitoring field has led to a proliferation of ad
hoc and proprietary database formats, prevent-
ing data from one manufacturer being com-
pared with data from another. A reasonable so-
lution to this problem is to make the database
formats available in an open-source manner,
and label the categories with an agreed subset
of the UMLS. However, manufacturers often
allow the customer (i.e., the clinical team) to
 ME63CH32-Clifford ARI 12 December 2011 14:21
extend the database format during use, seriously
affecting the ability of automated algorithms to
analyze the data.
Two final concerns with wireless patient
monitoring are worth noting. First, wireless
networks can introduce large delays (sometimes
several hours) in data transmission, and so pa-
tient data viewed on multiple devices can eas-
ily become unsynchronized. Synchronization
of databases has long been an issue with dis-
tributed software, and techniques from this field
may be valuable in dealing with such issues.
Second, wireless transmission of data raises is-
sues of patient privacy—particularly the risk
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of interception of patient data during wire-
less transmission. The definition of “private”
medical data or “protected health information”
varies significantly. Some countries have no pri-
vacy standards at all, and clinicians transmit pa-
tient data via public email accounts without en-
cryption; at the other extreme, even an ECG
without any identifiers is considered “private
data” in the United Kingdom. The potential for
international telemedicine is therefore some-
what complicated.
QUANTIFYING THE IMPACT
OF WIRELESS HEALTHCARE
Bondmass et al. (46) claimed to have completed
the first study of telemedicine for home mon-
itoring that reports clinical and economic out-
comes. Patients in this study measured their
own vital signs during telephone consultations
with nurses. Alarms were generated whenever
vital signs exceeded predefined upper or lower
thresholds, and these alarms were passed to
clinical staff in the study hospital.
De Lusignan (47) conducted a study of
20 patients, wirelessly recording HR, BR, BP,
ECG, and temperature, with results collected
at a central monitoring station. Vital-sign
accuracy was compared with periodic man-
ual measurements made by a nurse. The au-
thors concluded that the objectivity associ-
ated with collecting patient data via continuous
home monitoring is one of its advantages over
systems that require patients’ cooperation in
making measurements.
Stewart et al. (48) noted that 1% of the Na-
tional Health Service budget is devoted to heart
failure management, with 60% of this spent on
hospital admission. Most patients with heart
failure are managed by primary care physicians.
The authors emphasized that a ten-minute con-
sultation with a general practitioner is proba-
bly insufficient for accurate diagnosis and man-
agement of heart failure, and that avoidance of
“white coat syndrome” (the anomalously high
BP reading that results from the stress of the
clinical examination) should motivate the use
of home monitoring. The authors conducted a
20-patient study in which check-ups with nurs-
ing staff via video conferencing took place once
per week.
Woodend et al. (49) conducted a random-
ized controlled trial testing the effect of three
months of care via home monitoring, which col-
lected 12-lead ECG during video consultations
with clinical staff. The authors reported im-
proved patient outcomes. Louis et al. (50) sur-
veyed “telemonitoring” methods for patients
who have suffered chronic heart failure. At least
30% of patients diagnosed with heart failure
upon hospital discharge are readmitted within
three months, and up to 54% are readmit-
ted within six months. Admissions are typi-
cally prolonged and recurrent. Rich et al. (51)
and Stewart et al. (48) showed that daily vis-
its to patients’ homes by a nurse improved pa-
tient outcomes and reduced readmission rates.
Uncontrolled studies have shown patient ac-
ceptability of home monitoring ranging from
80% to 90% and have reported reductions
in hospital readmission rates, improvement in
patient quality of life, and a resultant over-
all decrease in annual medical costs due to
the reduction in readmission rate. The authors
concluded that larger, randomized trials are re-
quired in order to confirm these findings. They
attributed the benefits of home monitoring to
factors such as detecting new-onset atrial fibril-
lation, persistent hypotension, and overdiure-
sis (by measuring weight as a measure of fluid
balance).
www.annualreviews.org • Wireless Technology in Medicine 487
 ME63CH32-Clifford
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ARI 12 December 2011 14:21
Koch (52) surveyed 578 studies published
between 1990 and 2003 on the subject of “home
telemedicine,” noting that “most publications
deal with vital-sign measurement and au-
dio/video consultations.” The author observed
that “publications about . . . decision support for
staff are relatively sparse.” The clinical applica-
tion domains were mostly in the monitoring of
patients with chronic diseases, the elderly, and
children. The survey concluded by noting the
limitations of home telemedicine, including the
lack of standards to combine incompatible in-
formation systems, the lack of a framework by
which such systems could be evaluated, and the
lack of proper guidelines for practical imple-
mentation of home monitoring.
A similar survey by Martinez et al. (53)
considered 13 randomized controlled trials, 10
nonrandomized controlled trials, and 19 un-
controlled trials or descriptive studies. The au-
thors observed that most of the studies reviewed
did not discuss technical feasibility or technical
problems. However, these trials used patient-
acquired vital signs, and the phrase “continu-
ous vital-sign measurement” was used to denote
daily measurements made by the patient us-
ing electronic devices (including the ECG; 54).
Even among studies based on patient-acquired
data, the authors concluded that “there are still
few published data on the feasibility and the im-
pact of home monitoring.”
Pare et al. (55) performed a meta-analysis
of 65 studies that took place between 1990
and 2006. Of these studies, 18 concerned pul-
monary conditions, 17 diabetes, 16 cardiac dis-
eases, and 14 hypertension. The results of this
analysis showed that “the magnitude and signif-
icance of the telemonitoring effects on patients’
conditions still remain inconclusive for all four
chronic illnesses.” The authors concluded that
effects on patient outcomes (e.g., decrease in
emergency visits, hospital readmissions, and
hospital length of stay) were “more consistent
in pulmonary and cardiac studies than diabetes
and hypertension.” Importantly, although pa-
tient compliance was reportedly high in all stud-
ies, compliance was seen to decrease through
time, which is of concern given that the condi-
488 Clifford · Clifton
tions being monitored are chronic. Little eco-
nomic analysis was performed in the 65 studies.
Most of the 65 studies did not involve random-
ization, and only 8% included a control group.
The majority of studies collected data once per
day or once per week and included vital-sign
data. The authors also concluded that the qual-
ity and reliability of data acquired in the studies
were similar to those obtainable by clinical staff,
and that, given the weight of evidence provided,
future studies need not continue investigating
the quality of transferred data. The authors’
definition of “telemonitoring” included mea-
surement of physiological parameters with
the active involvement of the patient, rather
than entirely passive monitoring. Although the
majority of these studies required patients to
actively manage their data acquisition, alerts
based on univariate thresholds could be gener-
ated if measurements were sufficiently “abnor-
mal,” with those alerts then automatically sent
to clinicians for attention (56). Some studies
(57) have measured parameters continuously
using implanted sensors. Outcomes also appear
to have improved for patients implanted with
a “CardioMEMS” BP-measuring device (58).
A survey of publications on home telemoni-
toring for respiratory conditions between 1966
and 2007 found 23 relevant studies (59), of
which 7 pertained to patients undergoing pul-
monary transplantation, 12 were related to
asthma sufferers, and 4 involved patients with
COPD and other severe respiratory illnesses.
Eight of the 23 studies were randomized tri-
als. As in other reviews, these studies required
patient intervention in order to perform physi-
ological measurements, which were then trans-
mitted via various means to clinicians.
The case for mHealth in particular has
yet to be proven, although evidence is begin-
ning to surface in much the same manner as
for more traditional wireless monitoring. Part-
ners in Health have demonstrated that drug
stock-outs and overstocking (with consequent
improvement in mortality and costs) can be
achieved through increasing the speed of trans-
mission of HIV-related data and recording an-
tiretroviral usage (60). Another recent example
 ME63CH32-Clifford ARI 12 December 2011 14:21

is that of Pésinet (61), which uses mobile phones
to provide a preventive medical diagnostic for
children between 0 and 5 years of age. Local
staff in Senegal and Mali use a simple mobile
phone interface to enter and transmit informa-
tion about the infants’ weights and symptoms
(e.g., fever) to pediatricians via SMS. The rapid
and consistent transmission of data that indi-
cate the early stages of health problems (such
as malnutrition) has led to a claimed reduction
in mortality (in one group of 300 subjects in
Senegal) from 120 per 1000 to 8 per 1000. That
is, in over 90% of cases, if the disease is quickly
reported, the child will survive (61).
Annu. Rev. Med. 2012.63:479-492. Downloaded from www.annualreviews.org
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“apps” developed for the iPhone, many of
them are simply cosmetic and add little or
no additional value above the ability to re-
view data on a smaller, more portable screen.
Interestingly, it is the poorer health sectors
(and the associated nongovernmental organi-
zations) that have been driving much of the
revolution in low-cost mHealth. The rapid and
exciting changes that are occurring in emerg-
ing economies, necessitated by economic and
environmental constraints, may even provide a
model for developed economies to lower health
costs and increase efficiencies. The leapfrog ef-
fect in wireless telecommunication may trans-

late into a leapfrog effect in medicine. However,

CONCLUSIONS
The landscape of wireless monitoring for dis-
ease management is extremely complex and
rapidly evolving. Perhaps the most exciting as-
pects are the newer developments in mHealth.
Although the focus is often on visually exciting
large field trials are still required to prove the ef-
ficacy of mHealth. Moreover, much of the suc-
cess of wireless monitoring projects depends on
the human intermediaries who control and use
the data, and consideration of the human fac-
tors is essential for any successful deployment
of a wireless monitoring solution.

DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings that
might be perceived as affecting the objectivity of this review.

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Annual Review of
Medicine

Contents Volume 63, 2012

Huntington’s Disease: Advocacy Driving Science

Nancy S. Wexler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Direct-to-Consumer Genetic Testing: Perceptions, Problems,
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Timothy Caulfield and Amy L. McGuire p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p23
Human Genome Sequencing in Health and Disease
Claudia Gonzaga-Jauregui, James R. Lupski, and Richard A. Gibbs p p p p p p p p p p p p p p p p p p p p p35
The Genetic Architecture of Schizophrenia: New Mutations
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CCR5 Antagonism in HIV Infection: Current Concepts
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New Paradigms for HIV/AIDS Vaccine Development
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Emerging Concepts on the Role of Innate Immunity in the Prevention
and Control of HIV Infection
Margaret E. Ackerman, Anne-Sophie Dugast, and Galit Alter p p p p p p p p p p p p p p p p p p p p p p p p p 113
Immunogenetics of Spontaneous Control of HIV
Mary Carrington and Bruce D. Walker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
Recent Progress in HIV-Associated Nephropathy
Christina M. Wyatt, Kristin Meliambro, and Paul E. Klotman p p p p p p p p p p p p p p p p p p p p p p p p 147
Screening for Prostate Cancer: Early Detection or Overdetection?
Andrew J. Vickers, Monique J. Roobol, and Hans Lilja p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
Targeting Metastatic Melanoma
Keith T. Flaherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 171
Nanoparticle Delivery of Cancer Drugs
Andrew Z. Wang, Robert Langer, and Omid C. Farokhzad p p p p p p p p p p p p p p p p p p p p p p p p p p p p 185

v
 ME63-frontmatter ARI 20 December 2011 12:3

Circulating Tumor Cells and Circulating Tumor DNA

Catherine Alix-Panabières, Heidi Schwarzenbach, and Klaus Pantel p p p p p p p p p p p p p p p p p p p 199
Translation of Near-Infrared Fluorescence Imaging Technologies:
Emerging Clinical Applications
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Familial and Acquired Hemophagocytic Lymphohistiocytosis
G.E. Janka p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233
The Management of Gastrointestinal Stromal Tumors: A Model
for Targeted and Multidisciplinary Therapy of Malignancy
Heikki Joensuu and Ronald P. DeMatteo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247
Carotid Stenting Versus Endarterectomy
Annu. Rev. Med. 2012.63:479-492. Downloaded from www.annualreviews.org
by University of Oxford - Bodleian Library on 01/24/12. For personal use only.

David Doig and Martin M. Brown p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 259

Mitral Valve Prolapse
T. Sloane Guy and Arthur C. Hill p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
Telomeres, Atherosclerosis, and the Hemothelium: The Longer View
Abraham Aviv and Daniel Levy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Aquaporins in Clinical Medicine
A.S. Verkman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303
Role of Endoplasmic Reticulum Stress in Metabolic Disease
and Other Disorders
Lale Ozcan and Ira Tabas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Role of Fructose-Containing Sugars in the Epidemics of Obesity
and Metabolic Syndrome
Kimber L. Stanhope p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Vaccines for Malaria: How Close Are We?
Mahamadou A. Thera and Christopher V. Plowe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Crisis in Hospital-Acquired, Healthcare-Associated Infections
David P. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Novel Therapies for Hepatitis C: Insights from the Structure
of the Virus
Dahlene N. Fusco and Raymond T. Chung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 373
Multiple Sclerosis: New Insights in Pathogenesis and Novel
Therapeutics
Daniel Ontaneda, Megan Hyland, and Jeffrey A. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 389
Traumatic Brain Injury and Its Neuropsychiatric Sequelae
in War Veterans
Nina A. Sayer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405

vi Contents
 ME63-frontmatter ARI 20 December 2011 12:3

Eosinophilic Esophagitis: Rapidly Advancing Insights

J. Pablo Abonia and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 421
Physician Workforce Projections in an Era of Health Care Reform
Darrell G. Kirch, Mackenzie K. Henderson, and Michael J. Dill p p p p p p p p p p p p p p p p p p p p p p p 435
Reducing Medical Errors and Adverse Events
Julius Cuong Pham, Monica S. Aswani, Michael Rosen, HeeWon Lee,
Matthew Huddle, Kristina Weeks, and Peter J. Pronovost p p p p p p p p p p p p p p p p p p p p p p p p p p p p 447
Relationships Between Medicine and Industry: Approaches to the
Problem of Conflicts of Interest
Raymond Raad and Paul S. Appelbaum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
Wireless Technology in Disease Management and Medicine
Annu. Rev. Med. 2012.63:479-492. Downloaded from www.annualreviews.org
by University of Oxford - Bodleian Library on 01/24/12. For personal use only.

Gari D. Clifford and David Clifton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479

Geographic Variation in Health Care
Tom Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 493
Deep Brain Stimulation for Intractable Psychiatric Disorders
Wayne K. Goodman and Ron L. Alterman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
Contemporary Management of Male Infertility
Peter J. Stahl, Doron S. Stember, and Marc Goldstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 525

Indexes

Cumulative Index of Contributing Authors, Volumes 59–63 p p p p p p p p p p p p p p p p p p p p p p p p p p p 541

Cumulative Index of Chapter Titles, Volumes 59–63 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 545

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://med.annualreviews.org/errata.shtml

Contents vii

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