Invasive and non-invasive measurement in medicine and biology:

calibration issues
P Rolfe, a, b, c, Yan Zhanga, Jinwei Suna
F Scopesic, G Serrac
d
K Yamakoshi , S Tanakad, T Yamakoshid, Y Yamakoshid, M Ogawad
a
Dept. of Automatic Meas. & Control, Harbin Institute of Technology, China
b
Oxford BioHorizons Ltd. UK
c
Gaslini Institute, University of Genova, Italy
d
Kanazawa University, Kanazawa, Japan
ABSTRACT
Invasive and non-invasive measurement sensors and systems perform vital roles in medical care. Devices are based on
various principles, including optics, photonics, and plasmonics, electro-analysis, magnetics, acoustics, bio-recognition,
etc. Sensors are used for the direct insertion into the human body, for example to be in contact with blood, which
constitutes Invasive Measurement. This approach is very challenging technically, as sensor performance (sensitivity,
response time, linearity) can deteriorate due to interactions between the sensor materials and the biological environment,
such as blood or interstitial fluid. Invasive techniques may also be potentially hazardous. Alternatively, sensors or
devices may be positioned external to the body surface, for example to analyse respired breath, thereby allowing safer
Non-Invasive Measurement. However, such methods, which are inherently less direct, often requiring more complex
calibration algorithms, perhaps using chemometric principles. This paper considers and reviews the issue of calibration
in both invasive and non-invasive biomedical measurement systems. Systems in current use usually rely upon periodic
calibration checks being performed by clinical staff against a variety of laboratory instruments and QC samples. These
procedures require careful planning and overall management if reliable data are to be assured.
Keywords: Bio-medical measurement; sensors; calibration; invasive; non-invasive; medical devices.

1. INTRODUCTION
Specialised sensors and instruments, which have been steadily evolving over more than a century, are now used widely
to aid in the diagnosis and treatment of medical conditions, as well as to contribute to advancing the fundamental
understanding of normal and pathological conditions [1]. There is a diverse range of applications, for example the
haemodynamic monitoring of cardiac patients [2], monitoring of the fetus and the newborn baby [3], ambulatory
measurement in rehabilitation care [4], and measurement of the dose given in radiotherapy for cancer treatment [5]. In this
paper we are particularly concerned with measurements made directly in or on the subject of interest in vivo
measurement - and a selection of the possible measurands of relevance is shown in Table 1. These firstly include
chemical species that are related to critical processes in the subject, such as inspired oxygen, blood pH, and blood
glucose. The physical measurands shown here are relevant to a number of physiological processes, such as control of
blood pressure, breathing, and movement. Various types of radiation are used for both measurement and therapy,
including alpha and beta radiation in cancer treatment, and infra-red (IR) radiation for tissue analysis.
Table 1. A selection of target measurands for biomedical measurement in a wide variety of applications.

Chemical measurands

O2, CO2, H+, K+, Na+, glucose, urea, cholesterol

Physical measurands

Pressure, force, flow, displacement, activity, posture, temperature

Radiation

X-ray, alpha, beta, gamma, IR, UV

Biopotentials

ECG, EEG, EMG, EOG

Professor Peter Rolfe: E-mail PeterRolfe@aol.com

The sensors and instruments that have been developed are based upon a similarly wide range of operating principles,
including optics, photonics, and plasmonics, electro-analysis, magnetics, acoustics, bio-recognition, and bio-potentials
[6]
.
In each application area there are particular needs and constraints, especially in terms of precision and accuracy. For
example, for continuous real-time monitoring of dynamic changes it is often sufficient to have semi-quantitative or
qualitative information in the form of trends. By contrast, highly precise determination of certain measurands, such as
blood pH, is needed in other situations. In exploring this important issue here we categorise sensors and instruments on
the basis of whether they are positioned inside the patient - Invasive - or are external or on the surface of the body - NonInvasive. This categorisation is useful since it will usually dictate, or at least influence, safety and convenience as well as
precision and accuracy.
Performing invasive measurement involves the direct insertion into the human body of a sensor or probe. This approach
is very challenging technically, as sensor performance (sensitivity, response time, linearity) can deteriorate due to
interactions between the sensor materials and the biological environment, such as blood or interstitial fluid. Invasive
techniques may also be potentially hazardous, bringing risks of infection, haemorrhage, or thrombosis. Alternatively,
sensors or devices may be positioned external to the body surface, thereby allowing safer Non-Invasive Measurement.
However, these methods, which are inherently less direct, often require more complex calibration algorithms.
The matter of the accuracy of medical instruments has been the subject of discussion and investigation for some
considerable time. The methods for defining and reporting the accuracy of biomedical instrumentation have been
described and refined [7]. The importance of characterising instruments and procedures in terms of inter/intra observer
and instrument variation has been acknowledged and the need for quality control procedures emphasised [8]. However,
quality control in clinical measurement may often be a neglected subject, with even the simplest of calibration
procedures sometimes being overlooked or poorly carried out despite the obvious potential adverse impact on patient
safety.
In this paper we review the issues of instrument errors and calibration in both invasive and non-invasive biomedical
measurement systems.

2. DEVICE PERFORMANCE CHARACTERISTICS

Measurements made with both invasive and non-invasive devices are classified as in vivo measurements. Regardless of
whether the measurement is for research purposes or for clinical care it is important for users to know the likely error of
the data derived from their measurement system. The matters of measurement accuracy, sources or error, and calibration
procedures & practices are very much related to the more general topic of device performance. The European
Commission Directive on Medical Devices 93/42/ EEC makes specific reference to devices having a measuring function:
10. Devices with a measuring function
10.1. Devices with a measuring function must be designed and manufactured in such a way as to
provide sufficient accuracy and stability within appropriate limits of accuracy and taking account of
the intended purpose of the device. The limits of accuracy must be indicated by the manufacturer.
10.2. The measurement, monitoring and display scale must be designed in line with ergonomic
principles, taking account of the intended purpose of the device.
10.3. The measurements made by devices with a measuring function must be expressed in legal units
conforming to the provisions of Council Directive 80/181/EEC (1).
It would appear from this that the performance characteristics for biomedical measuring devices will generally have been
determined by the manufacturer and, where appropriate, users will have been provided with calibration curves and
certificates and possibly also with recommended test and calibration schedules. In certain applications there are
minimum performance standards specified by learned societies and national or international bodies (AAMI, AHA, BDA,
IEC, ISO, etc) and these may include indications of accuracy, drift, and frequency response, for example as would be
required for recording biopotentials such as the ECG and the EEG using surface mounted electrodes connected to
amplifiers and signal processing systems. Similar arrangements also exist for the measurement of blood pressure, both
with invasive and non-invasive devices.

The task of performing in vivo measurement, especially with invasive sensors, is challenging since the performance
characteristics may change significantly during use and thus the sensors and instruments must be assessed for their
performance appropriately. The methods used to achieve this assessment depend on the particular sensor or instrument
and on the application. In all of these cases there should be an aim to determine the precision and accuracy of the
measurement, thereby establishing the degree if uncertainty, identifying sources of error and minimizing their impact.

3. INVASIVE MEASUREMENT
3.1 Justification
Invasive measurement techniques are associated with certain risks but their use can be justified in several different
situations, including research investigations on animals or in clinical care of human subjects. Patients who are critically
ill e.g. during and following major surgery, can benefit from the rapid assessment of their condition that can best be
achieved with sensors placed directly into the vascular space or into tissues. Other patients may have certain chronic
conditions e.g. diabetes, requiring long-term surveillance and drug therapy. The purpose of this is to monitor some of the
most important physiological or control variables on a continuous basis so that rapid assessments can be made and
treatment optimised.
3.2 Sensor considerations
Appropriate invasive sensing devices for chemical and physical measurands are available for insertion into arteries,
veins, tissues and organs and typical features of these invasive sensors are shown in Table 2.
Table 2. Typical features of sensors used for invasive measurement.
Form; shape; size.

Flexible catheter/cannula; needle; cylindrical; disc-shaped; mm to m.

Response time

For rapid feedback of status: 1 sec to 1 min. For precise control: > 1 min

Calibration

Periodic cal-check against local laboratory instrument or standard.

Sensor life-time

24hrs to many months; single use disposable.

The sensing device could be in the form of a flexible polymer catheter (see Fig 1) for insertion into an artery, a vein, or a
tissue space such as the gastro-intestinal tract or the cerebro-spinal fluid Sensors constructed within hypodermic needles
are suitable for insertion into tissues, including sub-cutaneous regions. Flat or disc-shaped sensors are suitable for longterm implantation into tissues and organs, as the brain or heart.
The dimensions of the overall device are dictated by the application and may be several mm to more than 1 cm.
However, the sensor per se may be only a few 10s of microns or even nm.

Figure 1 This shows the general form of an invasive sensor. Flexible polymer catheters can be used to house invasive
sensors. The element at the tip may be an electrochemical sensor (amperometric or potentiometric), for example for
PO2, PCO2, H+, K+, Na+, urea or glucose. Fibre optic sensors may also be used (fluorimetric, colorimetric,
spectrophotometric), for example to measure PO2, sO2, PCO2, pH, or glucose. A blood sampling lumen allows samples
to be withdrawn for in vitro analysis. The sensing element may also be a semiconductor pressure transducer or FabryPerot pressure transducer. The lumen can be perfused with heparinised saline to allow pressure to be measured with an
external pressure transducer.

Chemical sensing (e.g. O2, CO2, H+, K +, glucose, urea, etc), may be based on amperometry, potentiometry, fluorescence,
spectrophotometry, immobilised enzymes or biological recognition elements.
Direct measurement of arterial and venous blood pressure is a vital part of intensive and critical care and is also needed
in cardio-diagnostics. It requires insertion, either, of a saline-filled catheter connected to an external pressure transducer,
or, of a catheter-tip pressure sensor. In the former case the hydraulic properties of the complete system must be taken
into account in order to achieve the desired frequency response for accurate recording of the dynamic aspects of the
blood pressure. The use of a catheter-tip pressure sensor overcomes this problem. Implanted pressure sensors in general
are based on piezo-electric/resistive or optical phenomena. Invasive devices for blood flow measurement primarily
utilise ultra-sound, laser Doppler-shift or electro-magnetic phenomena. These devices can be inserted into the vascular
system or the oesophagus or may be implanted within the heart or brain.
3.3 Operational performance & calibration
Invasive sensors are classified further in the EC Medical Devices Directive according to the duration of use, that is:
Transient continuous use for less than 60 mins; Short term continuous use for not more than 30 days; Long term
continuous use for more than 30 days. This classification is important with regard to the matter of the stability of the
device and the calibration protocol. Invasive sensors are in contact with the biological environment, be that blood in the
vascular space, interstitial fluids in tissue, or other fluids such as saliva, urine, cerebro-spinal fluid, or gastric fluids.
Interactions take place between the invasive sensor surfaces and the surrounding biological fluids, for example proteins
will be adsorbed to the sensor surface, cells can then adhere and this can lead to a coating of the sensor or encapsulation.
The bio-interaction events at sensor surfaces can lead to drift of calibration or, especially in the case of chemical sensors,
even to complete failure of the sensor. User protocols need to take account of the limitations of the sensor in each
particular application. Calibration of sensors in Transient use, that is for up to 60 mins of in vivo operation, will usually
rely on an initial in vitro calibration prior to insertion. This can involve the placement of the sensor into an appropriate
calibration chamber, for example a gas tonometer or a pressure chamber. Alternatively, some devices may be calibrated
in vivo immediately after insertion. For example, in the case of intra-vascular chemical sensors a blood sample can be
taken, analysed using a laboratory instrument 9 and the in vivo sensor then calibrated against the result obtained. This
approach can be used for devices measuring O2, CO2, pH, glucose and a number of other chemical measurands. The in
vivo pressure transducers can be subject to two-point calibration using a Hg sphygmomanometer as the reference
instrument. The degree of non-linearity of the pressure transducer will be specified by the manufacturer.
Invasive devices employed for Short term use, that is for up to 30 days of in vivo operation, must have calibration checks
performed periodically throughout the operational period. Typical devices might be arterial or venous catheters with
incorporated sensing elements for pressure or flow, or for a variety of chemical compounds. The verification of accuracy
during such a period of operation can be based on the same procedure as for Transient use devices, that is through
comparison with samples analysed in the local laboratory for chemical sensors or with a sphygmomanometer for
pressure. Maintaining a log of the calibration drift and the device sensitivity change with time is an important aspect of
overall performance evaluation, enabling decisions to be taken about the possible removal of the device from the subject
and replacement with a fresh device. This approach becomes especially important for devices in Long term use, which
involves continuous operation for more that 30 days. In fact, at present there are few sensors that are suitable for such
Long term operation, reflecting the difficulty of designing and manufacturing devices capable of withstanding the
biological environment and performing reliably.

4. NON-INVASIVE MEASUREMENT
4.1 Motivation
There are obvious advantages for biomedical measurement devices that do not need to be inserted into the subject,
including convenience and safety. Furthermore, such devices are not likely to have any major influence on the target
measurands or the process being examined. Thus, in the clinical arena especially, there has been a trend over several
decades to develop and use where possible non-invasive measurement devices [10], [11]. Several methods are already well
established, for example the measurement of biopotentials (ECG, EMG, EEG), which are straightforward to record with
skin-mounted electrodes. In this case calibration relates to the standardisation of amplifier gain and system frequency
response and is uncomplicated. However, in other important non-invasive devices the matter of calibration and data
verification is far less straightforward.

Figure 2. This shows the concept of a non-invasive device in contact with the skin surface. Interrogation of structures and
chemical compounds within the tissue can be achieved with various sensing principles, including electroanalysis,
photonics, electrical impedance, ultrasound, iontophoresis. (s.c. stratum corneum; s.b. stratum basale.)

4.2 Key non-invasive approaches

There is a vast array of non-invasive biomedical measurement devices and it is useful to consider these as falling into
one of two main types. Firstly, there are methods in which a device is in direct contact with the body surface [12].
Secondly, there are so-called contact-less approaches [13]. Some versions of the latter type are particularly suitable for the
surveillance of free-moving subjects. The definitions of these two types of non-invasive measurement device are neither
exact nor universally adopted in the literature and so the distinction between them sometimes becomes blurred. For
example, monitoring devices that are incorporated into clothing are sometimes referred to as non-contact devices even
though the clothing is of course in direct contact with the body.
Within the field of devices in contact with the body surface are approaches for the measurement of key chemical species,
especially O2, CO2, other gases and vapours, and glucose (see Figure 2). In so-called transcutaneous blood gas
monitoring electrochemical devices that are heated to around 40 C to produce local increased blood flow are able to
measure gases that diffuse through the skin from the underlying blood capillary network [14]. An extension of this method
is used to extract glucose via the skin with iontophoresis for measurement of glucose at the skin surface [15]. A further
substantial and very important group of contact methods is those based on optical analysis. Propagation of
electromagnetic radiation through tissues allows non-invasive measurements to be made based on absorption, scattering,
and fluorescence and systems using near infra-red spectroscopy (NIRS) [16] and pulse oximetry [17] have been developed
and are used clinically.
Non-invasive cardio-respiratory monitoring can be achieved with electrodes connected to the chest and/limbs.
Transthoracic electrical impedance measurement via these electrodes allows either, depth and frequency of breathing to
be monitored, as in impedance pneumography [18], or, cardiac output to be measured, as in impedance cardiography [19].
Indeed electrical impedance techniques can offer many possibilities in non-invasive measurement, including body
composition and also for imaging, as with electrical impedance tomography (EIT). Perhaps the most important noninvasive means of assessing cardiac performance over the last century has been the sphygmomanometer for measuring
arterial blood pressure with an inflatable limb-encircling cuff connected to a Hg-in-glass column. Modern technology has
steadily been introduced, for example to replace the Hg-in-glass column and to automate the measurement process.
Devices for the continuous monitoring of arterial blood pressure using a finger cuff instead of the limb-encircling cuff
have also been developed [20].
Access to respired gases and vapours by means of a facemask or nasal canula allows comprehensive respiratory
assessment to be carried non-invasively. Hot-wire or mesh screen anemometers are used for gas flow measurement and
pressures can be measured with appropriate semiconductor pressure transducers [21]. Processing of the signals to derive
work of breathing and lung mechanics parameters gives data useful for clinical diagnosis and treatment and for research.
Analysis of respired breath is of growing interest for non-invasive surveillance, including for the detection of cancer [22],
and it demands high sensitivity and means for recognition of molecular fingerprints to detect biomarkers of specific
diseases. This can be achieved with the use of arrays of sensors, based on electro-analysis or photonics, together with
neural networks.

4.3 Calibration and data verification issues

By their very nature non-invasive measurement devices are remote from the target measurands and this often presents
difficulties with calibration. For example, transcutaneous oxygen or carbon dioxide sensors are designed to give an
indication of the oxygen and carbon dioxide levels in the arterioles within the dermal layer beneath the skin-mounted
sensor. For oxygen we can represent this situation as:

PtcO2 = kPa O2

(1)

where Ptc O2 is the skin surface oxygen partial pressure and Pa O2 is the central arterial oxygen partial pressure. The
proportionality constant, k, embraces all physiological factors that can influence the relationship between skin surface
and arterial oxygen levels and this particularly includes skin blood flow and skin oxygen diffusion characteristics. In
! the accuracy of the sensor itself must also be taken into account and calibration
addition to these physiological factors
protocols are needed for this.
!
Photonics-based non-invasive measurement in tissues is possible for chemical compounds such as oxy and deoxy
haemoglobin, glucose, and cholesterol. This is achieved by transmission or reflection measurement together with some
form of computation, such as the multi-variate analysis employed in spectrophotometry. This will involve the
establishment of a calibration model from comparisons between the photonic measure and a standard, followed by
predictions of the measurand from when new photonic data sets are input to the model [23]. Clearly the ways in which
such systems are evaluated for accuracy are very different to the more straightforward approach used with simple
sensors. The calibration of sensor array systems used for breath analysis often relies upon a multivariate calibration
model, with user checks performed periodically against certified gas mixtures. This approach follows the concepts used
in natural biological olfactory systems in which libraries of the fingerprints of target molecules are established [24].

5. DISCUSSION
In vivo measurement, using either invasive or non-invasive devices, can make very important contributions to both basic
biomedical research and clinical care, but is accompanied by a number of challenges in terms of data quality. Although
the accuracy of in vivo measurement systems, and the verification of this through appropriate calibration regimes, would
seem to be the sine qua non of professional and well-organised implementation, this important matter is often not given
sufficient attention.
The safety of medical electrical equipment used for diagnosis or control of therapy is a shared responsibility for all
parties involved in the chain from development, manufacture, user training, in service accuracy verification, and
maintenance and repair. An important overarching role is that of the of Regulatory and Standards authorities, the
International Electrotechnical Commission (IEC) and the International Organisation for Standardisation (ISO), and of
direct relevance here is the general standard for medical electrical equipment, IEC 60101-1, and the growing family of
collateral standards for particular types of medical electrical equipment, X, referenced as IEC 60101-1-X.
The measurement of blood pressure represents perhaps one of the most important and long-standing clinical practices
and it is therefore not surprising that this has been given considerable attention with respect to standards. With direct
blood pressure measurement using invasive approaches the accuracy may be significantly influenced by how careful the
clinical users are in ensuring transducer zeroing and freedom of air bubbles in the hydraulic tubing [25]. The latter can be
minimised with the use of miniature pressure sensors. The IEC is involved in developing a standard for invasive BP
measurement under the reference IEC 60601-2-34 [26].
Non-invasive blood pressure measurement, using a limb-encircling cuff or a finger cuff, is carried out widely, and
measurement precision and accuracy are influenced by cuff dimensional factors and signal processing algorithms. As a
result there has been considerable interest in the matter of calibration in the field of non-invasive BP measurement [27].
This matter is included in several related standards, for automated and non-automated non-invasive blood pressure
measurement devices. ISO 81060-1:2007 covers the requirements and test methods for non-automated measurement
types [28]. BS EN 1060-4:2004 deals with test procedures for determining the overall system accuracy of automated
sphygmomanometers [29]. BS ISO 81060-2:2009 deals with the clinical validation of such automated devices [30] and
covers sphygmomanometers intended for use in all patient populations (e.g. all age and weight ranges), and all
conditions of use including ambulatory blood pressure monitoring, stress testing blood pressure monitoring and blood
pressure monitors for the home healthcare environment or self-measurement. As non-invasive devices increasingly find

their way into the health screening field, including use in the home, new standards are being introduced and of relevance
here is IEC 60601-1-11:2010 [31]. This is concerned with general requirements for basic safety and essential performance
for medical electrical equipment and medical electrical systems used in the home healthcare environment.
Blood gas and pH measurement are vital in critical care situations and real-time monitoring with invasive or noninvasive devices can provide useful dynamic data. The calibration of invasive devices against withdrawn blood samples
relies on the performance of the laboratory blood gas analyzer and on the care of clinical staff in withdrawing valid
samples. Surprisingly, almost all papers published on the comparison between invasive sensor measurements with
laboratory analysis of withdrawn samples do not define or comment on the precision and accuracy of the laboratory
analyser used [32]. However, guidelines and recommendations for the calibration and quality control of point-of-care
blood gas analysers have been introduced by a number of national and international bodies [33]. This is also important for
the in vivo verification or testing of non-invasive blood gas monitoring devices, such as transcutaneous O2 and CO2
sensors and pulse oximeters. In fact there are international standards relating to both of these types of non-invasive
device [34] [35].
Perhaps as important as blood pressure measurement is the whole filed of glucose monitoring, implemented either with
implanted sensors or with non-invasive skin-mounted probes. These approaches have the potential to give the most
realistic view of the dynamic nature of actual, central, glucose fluctuations during normal daily life. However, there are
still needs to establish effective calibration protocols and standards for continuous glucose monitoring systems [36]. Also
there are acknowledged problems in the need to calibrate transdermal glucose measuring devices against invasive blood
sampling and analysis on a once per day basis [37]. The community awaits the arrival in the market of truly non-invasive
glucose measurement and no doubt when this happens there will be similarly complex challenges concerning calibration.
The field of in vivo biomedical measurement is large and is continually growing. It encompasses all organs and tissues
and the physiological processes thereof, has led to exciting innovations in the measurement science and technology. Yet
challenges remain concerning the procedures and practices needed to assure the validity of the data derived so that
patient safety is not compromised. Examples are many and various. Intra-ocular pressure is measured non-invasively
routinely in order to detect raised pressure associated with the very dangerous condition of glaucoma. Studies to
investigate the accuracy of instruments during use reveal that in many cases calibration procedures are not adhered to
and resulting errors can be sufficiently large to lead to false positive and false negative screening outcomes [38].

6. CONCLUSIONS
Invasive and non-invasive measurement sensors and systems perform vital roles in medical care. They generally rely
upon periodic calibration checks being performed by clinical staff against a variety of laboratory instruments and QC
samples. These procedures require careful planning and overall management if reliable data are to be assured. There can
be substantial differences between simultaneous measurements of the same measurand by invasive and non-invasive
means and this usually reflects, firstly, the possible influence of the invasive sensor on the measurand and, secondly, the
indirect nature of the non-invasive method.

ACKNOWLEDGEMENTS
The authors are grateful for support from Harbin Institute of Technology, China, The G Gaslini Foundation, Italy,
OBHL, UK, and Kanazawa University, Japan.

REFERENCES

[1]
[2]
[3]

Payne P.A., Editor, Concise Encyclopedia of Biological & Biomedical Measurement Systems, Pergamon Press,
(1991).
Malfatto G., Branzi G., Giglio A., Villani A., Facchini C., Ciambellotti F., Facchini M., Parati G. Transthoracic
bioimpedance and brain natriuretic peptide levels accurately indicate additional diastolic dysfunction in patients
with chronic advanced systolic heart failure. Eur J Heart Fail [Epub ahead of print] (2010).
Rolfe P., Scopesi F. and Serra G. Biomedical Instruments for Fetal and Neonatal Surveillance. J. Phys:
Conference Series, 48:11311136, (2006)

[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]

Motoi K., Tanaka S., Kuwae Y., Yuji T., Higashi Y., Fujimoto T., and Yamakoshi K. Evaluation of a wearable
sensor system monitoring posture changes and activities for use in rehabilitation. J. Robotics and Mechtronics,
19:656-666, (2007).
Scarantino C.W., Rini C.J., Aquino M., Carrea T.B., Ornitz R.D., Anscher M.S., Black R.D. Initial clinical
results of an in vivo dosimeter during external beam radiation therapy. Int J Radiat Oncol Biol Phys.;62(2):60613, (2005).
Oberg P.A., Togawa T., Spelman F.A. eds. Sensors Application, Vol. 3 Sensors in Medicine and Health Care,
Wiley-VCH Verlag, Weinheim, (2004).
Latman N.S., Lanier R. Expressions of accuracy in the evaluation of biomedical instrumentation. Biomed
Instrum Technol. 32(3):282-8, (1998).
Colley R., Gorber S.C., and Tremblay M.S. Quality control and data reduction procedures for accelerometryderived measures of physical activity. Statistics Canada, Catalogue no. 82-003-XPE, Health Reports, Vol.
21(1):1-7, (2010).
Abraham E., Gallagher T.J., Fink S. Clinical evaluation of a multiparameter intra-arterial blood-gas sensor.
Intensive Care Med. Vol 22(5):507-13, (1996).
Rolfe P (1979) Editor; Non-Invasive Physiological Measurements, Vol I Academic Press, London.
Rolfe P (1983) Editor, Non-Invasive Physiological Measurements, Vol II Academic Press, London
Zhu X., Chen W., Nemoto T., Kanemitsu Y., Kitamura K., Yamakoshi K., and Wei D. Real-time monitoring of
respiration rhythm and pulse rate during sleep, IEEE Trans. Biomed. Eng., 53:2553-2563, (2006).
Dei D., Grazzini G., Luzi G., Pieraccini M., Atzeni C., Boncinelli S., Camiciottoli G., Castellani W., Marsili M.
and Dico J.L. Non-Contact Detection of Breathing Using a Microwave Sensor. Sensors 9:2574-2585, (2009);
doi:10.3390/s90402574.
Huch R, Huch A and Rolfe P Transcutaneous measurement of PO2 using electrochemical analysis. In NonInvasive Physiological Measurements. Ed P Rolfe, Academic Press London: pp 313-331, (1979).
Rao G, Glikfeld P, Guy RH. Reverse iontophoresis: development of a non-invasive approach for glucose
monitoring. Pharm. Res. 10:1711-1715, (1993).
Rolfe P. In Vivo Near Infra-Red Spectrophotometry. Annual Reviews in Biomedical Engineering, Vol 2: 31554, (2000).
Aoyagi T., Fuse M., Kobayashi N., Machida K., Miyasaka K.. Multiwavelength pulse oximetry: theory for the
future. Anesth Analg. 105(6 Suppl):S53-8, (2007).
Wolf G.K., Arnold J.H. Noninvasive assessment of lung volume: respiratory inductance plethysmography and
electrical impedance tomography. Crit Care Med. 33(3 Suppl):S163-9, (2005).
Wang D.J., Gottlieb S.S. Impedance cardiography: more questions than answers. Curr. Cardiol. Rep. 8(3):1806, (2006).
Yamakoshi K. Non-invasive cardiovascular hemodynamic measurements. In, Sensors in Medicine and Health
Care, Ed PA Oberg, T Togawa, and FA Spelman, Wiley-VCH Verlag, Weinheim, (2004).
Rolfe P., Scopesi F., Sun J., and Serra G. Physiological Monitoring in the Ventilated Neonate: A Rationale.
IFMBE Proc. Vol 19(9): 413-416 (2008). 10.1007/978-3-540-79039-6_104.
Di Natale, C., Macagnano, A., Martinelli, E., Paolesse, R., D'Arcangelo, G., Roscioni, C., Finazzi-Agro, A.,
D'Amico, A. Lung cancer identification by the analysis of breath by means of an array of non-selective gas
sensors. Biosens. Bioelectron. Vol 18: 12091218, (2003).
Yamakoshi K., and Yamakoshi Y. Pulse glucometry: A new approach for noninvasive blood glucose
measurement using instantaneous differential near-infrared spectrophotometry, Journal of Biomedical Optics
11(5), 054028-pp.1-9, (2006).
Machado R.F., Laskowski D., Deffenderfer O., et al Detection of Lung Cancer by Sensor Array Analyses of
Exhaled Breath, Am. J. Resp. and Crit. Care Med. Vol 171. pp. 1286-1291, (2005).
Powner D.J., John A.M. Technical aspects of intravascular pressure monitoring during donor care. Prog
Transplant. 20(1):22-6, (2010).
International Electrotechnical Commission. Medical electrical equipment - Part 2-34: Particular requirements for
basic safety and essential performance of invasive blood pressure monitoring equipment, IEC 60601-2-34.
Balestrieri, E., Rapuano, S. Standard calibration procedures for automated non-invasive measurement of blood
pressure. Int J Advanced Media and Comm, Vol. 3(1/2):236 246, (2009).

[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]

International Organisation for Standardisation. Non-invasive sphygmomanometers -- Part 1: Requirements and

test methods for non-automated measurement type, ISO 81060-1:2007.
British Standards Institute. Non-invasive sphygmomanometers Part 4. Test procedures to determine the overall
system accuracy of automated non-invasive sphygmomanometers, BS EN 1060-4:2004.
British Standards Institute. Non-invasive sphygmomanometers. Clinical validation of automated measurement
type, BS ISO 81060-2:2009.
International Electrotechnical Commission. Medical electrical equipment -- Part 1-11: General requirements for
basic safety and essential performance -- Collateral standard: Requirements for medical electrical equipment and
medical electrical systems used in the home healthcare environment, IEC 60601-1-11:2010.
Zollinger A., Spahn D.R., Singer T., Zalunardo M.P., Stoehr S., Weder W., Pasch T. Accuracy and clinical
performance of a continuous intra-arterial blood-gas monitoring system during thoracoscopic surgery, Br. J.
Anaesth., 79(1):47-52, (1997).
DOrazio P., Ehrmeyer S.S., Jacobs E., Toffaletti J.G., Wandrup J.H. Blood Gas and pH Analysis and Related
Measurements; Approved Guideline - Second Edition. CLSI document C46-A2, Vol 29(8), Clinical and
Laboratory Standards Institute, Pennsylvania, USA, (2009).
International Electrotechnical Commission. Medical electrical equipment - part 2-23: particular requirements for
the safety, including essential performance, of transcutaneous partial pressure monitoring equipment, IEC 606012-23 EN 60601-2-23.
British Standards Institute. Medical electrical equipment. Particular requirements for the basic safety and
essential performance of pulse oximeter equipment for medical use, BS EN ISO 9919:2005.
Nichols, J.H. and Klonoff, D.C. The Need for Performance Standards for Continuous Glucose Monitors. J
Diabetes Sci Technol. Vol. 1(1): 9294, (2007).
Sieg A., Guy R.H., and Delgado-Charro M.B. Noninvasive Glucose Monitoring by Reverse Iontophoresis in
Vivo: Application of the Internal Standard Concept. Clin. Chem. 50:1383-1390, (2004).
Choudhari N.S., George R., Baskaran M., Vijaya L., Dudeja N. Measurement of Goldmann applanation
tonometer calibration error. Ophthalmology, Vol 116:3 8, (2009).