Am J Nucl Med Mol Imaging 2015;5(5):527-547
`www.ajnmmi.us /ISSN:2160-8407/ajnmmi0014068
`
`Review Article
`Dosage optimization in positron emission tomography:
`state-of-the-art methods and future prospects
`
`Nicolas A Karakatsanis1,2, Eleni Fokou3, Charalampos Tsoumpas1,3
`
`1Translational and Molecular Imaging Institute and Department of Radiology, Icahn School of Medicine at Mount
`Sinai, New York, USA; 2Division of Nuclear Medicine and Molecular Imaging, School of Medicine, University of
`Geneva, Geneva, Switzerland; 3Division of Biomedical Imaging, University of Leeds, Leeds, United Kingdom
`Received August 6, 2015; Accepted September 4, 2015; Epub October 12, 2015; Published October 15, 2015
`
`Abstract: Positron emission tomography (PET) is widely used nowadays for tumor staging and therapy response in
`the clinic. However, average PET radiation exposure has increased due to higher PET utilization. This study aims
`to review state-of-the-art PET tracer dosage optimization methods after accounting for the effects of human body
`attenuation and scan protocol parameters on the counting rate. In particular, the relationship between the noise
`equivalent count rate (NECR) and the dosage (NECR-dosage curve) for a range of clinical PET systems and body at-
`tenuation sizes will be systematically studied to prospectively estimate the minimum dosage required for sufficiently
`high NECR. The optimization criterion can be determined either as a function of the peak of the NECR-dosage curve
`or as a fixed NECR score when NECR uniformity across a patient population is important. In addition, the systematic
`NECR assessments within a controllable environment of realistic simulations and phantom experiments can lead
`to a NECR-dosage response model, capable of predicting the optimal dosage for every individual PET scan. Unlike
`conventional guidelines suggesting considerably large dosage levels for obese patients, NECR-based optimization
`recommends: i) moderate dosage to achieve 90% of peak NECR for obese patients, ii) considerable dosage reduc-
`tion for slimmer patients such that uniform NECR is attained across the patient population, and iii) prolongation of
`scans for PET/MR protocols, where longer PET acquisitions are affordable due to lengthy MR sequences, with mo-
`tion compensation becoming important then. Finally, the need for continuous adaptation of dosage optimization to
`emerging technologies will be discussed.
`
`Keywords: PET, PET/CT, PET/MR, dosage, NECR, optimization, Monte-Carlo
`
`Introduction
`
`Imaging is nowadays considered an essential
`part of modern nuclear medicine procedures
`as it provides the means to obtain an abun-
`dance of multi-dimensional information for the
`diagnosis, prognosis and therapy response
`monitoring of a variety of diseases in the clinic
`[1]. In particular, positron emission tomography
`(PET) is an established imaging modality for the
`in-vivo inspection of a wide spectrum of diseas-
`es in oncology [2-4], cardiology [5] and neurol-
`ogy [6]. PET has gained considerable attention
`in the medical imaging community in the last
`few decades, over other nuclear imaging tech-
`niques, as most of the chemically relevant to
`human body radioisotopes are positron emit-
`ters (11C, 13N, 15O, 18F) and thus can more effi-
`ciently label pharmaceutical substances of
`
`physiological interest. Meanwhile, the signifi-
`cant evolution of PET scanner technology over
`the last decades enabled, for the first time, 3D
`multi-functional imaging of numerous molecu-
`lar and cellular biochemical processes [4].
`
`Despite the advantages of PET as a metabolic
`in-vivo imaging modality, acquisition of accu-
`rate and high-resolution anatomical informa-
`tion is currently not possible by PET alone due
`to underlying physical limitations, even when
`prolonging scan time through transmission
`acquisitions or when state-of-the-art time-of-
`flight (TOF) technology is employed. This has led
`to the introduction of hybrid scanners, such as
`PET/Computed Tomography (PET/CT) and PET-
`Magnetic Resonance (PET/MR) systems where
`the CT or MR modalities can be utilized to
`obtain the missing anatomical information.
`
`Petitioner GE Healthcare – Ex. 1037, p. 527
`
`

`

`Dosage optimization strategies in PET
`
`Additionally, the development of fully integrated
`multi-modality PET systems nowadays enables
`acquisition of anatomical maps that are per-
`fectly co-registered with PET images, thus
`allowing for the precise localization and attenu-
`ation correction of the PET signal, which is very
`important for quantitative imaging tasks and
`image-guided therapy [2].
`
`However, radiation exposure can be a serious
`concern for adult and particularly children
`patients, especially in the case of PET/CT hybrid
`systems, due to the ionizing nature of both PET
`and CT radiation, with the latter contributing to
`relatively higher absorbed doses than the for-
`mer modality. Previously, studies assessed the
`risk of radiation dose absorbed by the human
`tissue during whole-body PET and CT scans and
`proposed efficient PET dosage regimens to
`reduce the total exposure as much as possible,
`although exposure from CT remains significant
`[7, 8]. Fortunately with the advent of hybrid
`PET/MR imaging, the total radiation absorbed
`dose in clinic can be now significantly reduced
`thanks to the zero contribution of ionizing radia-
`tion by MR modality. Therefore, as PET/MR
`imaging becomes widely applicable, the main
`effort in further reducing absorbed dose to
`patients and personnel can be concentrated
`on the injected dosage minimization without
`degrading image quality (IQ). The decay rate, or
`activity, of a positron-emitting radiopharma-
`ceutical is a random process following the well-
`characterized Poisson distribution [9]. Thus,
`the acquisition of the PET data is a statistical
`imaging process characterized by a level of
`inherent uncertainty, which can be quantified
`with the statistical index of standard deviation
`[10]. According to the principles of Poisson dis-
`tribution, the relative percentage uncertainty in
`the detected coincidence rate is reduced with
`higher number of counts and thus, from a sta-
`tistical point of view, it is highly desirable to be
`able to achieve the maximum possible counts
`for a given amount of scan time or equivalently
`the highest count rate.
`
`However, the type of counts recorded during a
`PET acquisition can be classified as either true,
`scattered or random coincidence events, as it
`will be explained later, of which only the trues
`accurately reflect the actual underlying radio-
`nuclide activity distribution, while scattered
`and random events contaminate the total sig-
`
`nal with misleading information. Thus, a high
`number of overall detected coincidence events,
`also known as prompts, do not necessarily
`translate to higher statistical quality and signal
`to noise ratio (SNR) for the acquired PET raw
`data and respective reconstructed images.
`Instead, the index of noise-equivalent counts
`could be employed to quantify the net positive
`contribution or SNR of the prompts. Therefore,
`retaining a sufficiently high noise-equivalent
`count rate (NECR), as opposed to prompt
`counts rate, could be a more reliable strategy
`to ensure a high SNR for the measured PET
`data and the respective images for a given
`scan period.
`
`PET systems detect coincidence events at a
`particular rate for a given underlying activity
`distribution in the FOV [9, 11]. The measured
`total coincidences count rate per unit of total
`activity distribution in the FOV characterizes
`the sensitivity of a PET scanner [10]. Higher
`scanner sensitivity can indeed be one of the
`factors ensuring high NECR and SNR perfor-
`mance, but it is usually fixed for each PET sys-
`tem, thus leaving no margins of data quality
`optimization. However, another parameter that
`can drastically affect NECR for a given scanner
`and could be used for its optimization is the
`amount of administered radiopharmaceutical
`dosage [12-14]. Therefore, NECR and conse-
`quently SNR, can be significantly regulated for
`a given scanner or sensitivity, either to a maxi-
`mum or a sufficiently high value by administer-
`ing a proper amount of radiopharmaceutical
`dosage.
`
`Furthermore, the relationship between the
`administered dosage and the “statistically use-
`ful” count rate, i.e. the NECR, of a PET scanner
`may depend on a range of parameters which
`can be either scanner-related such as the geo-
`metric efficiency, detection efficiency, energy
`window and dead-time effect [11, 13] or
`patient-related, such as the degree of radiation
`attenuation caused by the body and the rela-
`tive position between the targeted source dis-
`tribution and the current bed field-of-view (FOV)
`of the scanner [13]. By systematically and
`quantitatively analyzing the effects of these
`factors on NECR for a range of dosage levels,
`an accurate NECR-dosage response model can
`be designed allowing for the prediction of the
`minimum possible amount of dosage required
`
`528
`
`Am J Nucl Med Mol Imaging 2015;5(5):527-547
`
`Petitioner GE Healthcare – Ex. 1037, p. 528
`
`

`

`Dosage optimization strategies in PET
`
`to sufficiently maintain NECR, or statistically
`useful counts, at a quantitatively acceptable
`level. In the past, many studies [10, 14] system-
`atically examined the effect of these factors on
`different types of PET coincidence count rates
`(true, random, scatter) and the NECR.
`
`As a result, a possible strategy for the optimiza-
`tion of the administered dosage prior to every
`individual PET scan could consist of two essen-
`tial steps: i) Initially, a systematic assessment
`of the NECR response as a function of the
`administered dosage needs to be conducted
`for a family of clinical PET scanners and a vari-
`ety of patient- and scanner-related study
`parameters, as described above. This will
`enable the design of a parameterized model
`that can adequately describe the NECR-dosage
`relationship for a wide set of acquisition sce-
`narios often present in clinical routine. Then, ii)
`such model could be utilized to predict, for a
`given set of patient attenuation properties and
`scanner settings, an optimal range of dosage-
`levels for which a nearly maximal NECR is
`expected by the model. The terms “range of
`dosage” and “nearly maximal NECR” imply that
`the predicted outcome will initially be a range of
`dosages as opposed to a single value while
`the final dosage recommendation may corre-
`spond to a NECR value close to the peak,
`expressed as a user-defined percentage (%) of
`the latter, e.g. at least 90% of the peak NECR
`for the given set of parameters.
`
`However, the previous dosage regimen scheme
`may result in highly variable NECR scores
`among patient scans, as the criterion is a per-
`centage of the peak which may vary significant-
`ly across the scan populations, e.g. between
`slim and obese patients. Alternatively, a dose
`optimization strategy that would ensure NECR
`equivalency over a population of patient scans
`could utilize the same NECR-dosage response
`model to predict the amount of dosage that
`would induce a fixed NECR score for all scans,
`regardless of the patient and scanner factors
`involved. In that case, the optimal dosage
`would obviously not correspond to a maximal
`NECR for all cases, as the previous scheme, but
`would ensure a sufficient and uniform NECR
`performance across the population. The losses
`in NEC counts could then be compensated by
`accordingly elongating the PET scan duration.
`This could be applicable i) to some extent, to
`
`longer PET/CT protocols, but ii) more efficiently
`to simultaneous PET-MR protocols, where the
`lengthy MR acquisitions permit equally long
`PET acquisitions.
`
`Therefore, the aim of this review is to present a
`collection of studies demonstrating the feasibil-
`ity of NECR-based dosage optimization in indi-
`vidual PET studies, after systematically evaluat-
`ing the dosage effect on NECR for a representa-
`tive set of patient- and scanner- parameters.
`Thus, individualized prediction of optimal dos-
`age may become possible prior to every PET
`scan, paving the way for personalized multimo-
`dality PET clinical imaging protocols across a
`wide range of patients and scanner configu-
`rations.
`
`Critical analysis
`
`Coincidence types and their contribution to the
`actual PET information
`
`PET utilizes trace amounts of positron emitting
`radiopharmaceuticals (radio-tracers), such as
`18F-fluorodeoxyglucose (FDG) [2, 4, 15]. Each
`emitted positron travels a short distance
`(range) before it annihilates with an electron
`causing the emission of two gamma photons,
`each of 511 keV energy, at nearly opposite
`directions [16, 17]. Radiotracers emitting posi-
`trons of relatively low kinetic energy are pre-
`ferred to ensure minimum energy (dose) depo-
`sition at the point of emission and small trav-
`elled distance of the positron (positron range)
`before its annihilation. Subsequently, the two
`emitted gamma photons are detected in coinci-
`dence by two opposing PET detectors. The line
`connecting that pair of detectors is known as
`the line of response (LOR) for that coincident
`event and defines the geometrical space where
`the annihilation occurred [16, 17]. This type of
`coincidence event, called ‘true coincidence’, is
`the desired type of count in PET imaging, as it
`defines an LOR that includes the actual point of
`annihilation and thus positively contributes to
`the true or net PET signal [18]. However, there
`are also two other possible types of detection
`events, which are contaminating the overall
`PET signal with erroneous information: the
`scattered and random coincidences.
`
`Scattered coincidence events, simply denoted
`also as “scatter”, occur when at least one of the
`two emitted gamma photons undergoes
`
`529
`
`Am J Nucl Med Mol Imaging 2015;5(5):527-547
`
`Petitioner GE Healthcare – Ex. 1037, p. 529
`
`

`

`Dosage optimization strategies in PET
`
`Figure 1. Realistic digital framework of multiple simulated FDG-PET studies.
`The presented framework enables comparisons of realistic SUV values from
`reconstructed simulated PET images against the ground truth. Published with
`permission of the author and the Publisher. Originally published in Silva-Ro-
`driguez J, Aguiar P, Dominguez-Prado I, Fierro P, Ruibal A. Simulated FDG-PET
`studies for the assessment of SUV quantification methods. Rev Esp Med Nucl
`Imagen Mol 2015; 34(1): 13-8. Copyright © 2014 Elsevier España, S.L.U. and
`SEMNIM. All rights reserved [22].
`
`result, randoms are more
`likely observed at high-count
`rates where
`interference
`between different but near-
`ly simultaneous annihilations
`is more probable [20, 21].
`Therefore, random coinciden-
`ce detection rates depend on
`the rate of individual gamma
`photon detections, known as
`singles rate, which in turn,
`depends on
`the
`rate of
`gamma photon emissions
`(activity) within the field-of-
`view (FOV) [16]. In fact ran-
`doms rate is proportional to
`the square of singles rate,
`and
`thus
`it can become
`considerable at high activity
`concentration levels. Further-
`more, randoms are expected
`to increase with the coinci-
`dence time window (CTW)
`width of the scanner, which
`determines
`the maximum
`allowed difference in the esti-
`mated detection time bet-
`ween two singles event to be considered as a
`coincidence event [16]. The slower the detec-
`tion system is responding to a given rate of inci-
`dent gamma photons, the larger the uncertain-
`ty in estimating the exact time of detection and,
`thus the larger the CTW width has to be to mini-
`mize rejection of true coincidences. Con-
`sequently, for a given activity level, wider CTWs
`are expected to yield higher fraction of random
`events [16, 17, 19]. As a result, both scatter
`and random events reduce image quality (IQ) by
`degrading spatial resolution and contrast due
`to inaccuracies caused by LOR mispositioning
`[18].
`
`Standardized uptake value (SUV) metric and
`its limitation for image-based PET data quality
`assessments
`
`One important feature of PET imaging is its abil-
`ity to acquire quantitative estimates of in-
`vivo concentration of physiologically relevant
`radiopharmaceuticals which can later be used
`for a wide range of quantitative imaging tasks,
`e.g. for tumor characterization, differentiation
`and response to therapy in oncology [22]. The
`activity concentration measurements at every
`image pixel can be normalized with respect
`to the total administered PET tracer dosage
`
`Am J Nucl Med Mol Imaging 2015;5(5):527-547
`
`Compton scattering when interacting with the
`patient’s body or a detector crystal before its
`actual detection, causing it to change direction
`and thus divert from the true LOR while losing
`part of its kinetic energy deposited at detection
`point [16]. Scatter events may still be detect-
`able as coincidences, provided the energy of
`each scattered photon deposited in PET detec-
`tors still lies within the energy window account-
`ed by the PET system. However, the trajectories
`of two photons, of which at least one has under-
`gone Compton scattering, are no longer aligned
`with respect to each other, thus violating the
`basic assumption of 180-degree angle between
`them and resulting in mispositioned LORs [16,
`19]. The fraction of scatter to the total number
`of detected events, known as scatter fraction,
`depends on the attenuation properties of the
`imaging subject and detectors as well as the
`energy window of the system, the latter deter-
`mined by the finite energy resolution of the
`detection system.
`
`Similarly, random coincidence events, also
`known simply as “randoms”, may also trigger
`LORs mispositioning but through a different
`mechanism: the nearly simultaneous but acci-
`dental (random) detection of two gamma pho-
`tons produced by different annihilations. As a
`
`530
`
`Petitioner GE Healthcare – Ex. 1037, p. 530
`
`

`

`Dosage optimization strategies in PET
`
`and the lean body mass or weight of the patient
`to obtain the surrogate metric of standardized
`uptake value (SUV), a well-established index in
`clinical nuclear medicine [22]. However, SUV
`only reflects the normalized radioactivity con-
`centration present in the tissue of interest at a
`certain time. As a result, it should be pointed
`out that SUV may not be considered fully quan-
`titative, as it is inherently time-dependent and
`can be also influenced by various patient- and
`scanner-related parameter [23, 24].
`
`Recently, Silva-Rodriguez et al. (2015) present-
`ed a PET simulation framework (Figure 1) con-
`sisting of multiple FDG-PET realistic digital
`phantoms to enable systematic comparative
`SUV evaluations at various regions of interest
`(ROIs) between true input and reconstructed
`simulated PET images for three different SUV
`calculation methods [22]. Although the study
`showed the usefulness of SUV metric in evalu-
`ating clinically relevant tumor characteristics
`from PET images, it also demonstrated its high
`sensitivity to the partial volume effect and sta-
`tistical noise which can considerably affect
`detectability and quantification of
`tumor
`regions in the reconstructed PET images [22].
`
`The ALARA principle
`
`The general human population is daily exposed
`to low levels of ionizing radiation, relative to the
`safety limits, originated from the universe and
`long-lived radioisotopes in certain earth loca-
`tions. However, radiation exposure of the gen-
`eral population due to medical procedures has
`recently increased on average due to the more
`extensive usage of radiation
`in medicine,
`including nuclear medicine exams, mainly for
`the purpose of i) diagnosing diseases at earlier
`stages and assessing their progress, ii) evalu-
`ating treatment response and iii) designing
`optimal image-guided therapeutic schemes. In
`particular, absorbed radiation dose itself is an
`important parameter to study, because it may
`lead to deterministic or stochastic damaging
`radiobiological effects in living tissues if the
`safety limits are exceeded [25]. In particular,
`PET is associated with a relatively low radiation
`exposure to patients due to internal administra-
`tion of beta (positron) emitting radiopharma-
`ceuticals. The injected dosage is then distrib-
`uted over time across the human tissue while
`emitting gamma ionizing radiation due to the
`
`positron annihilation effect [26]. The amount of
`energy or dose deposited as a result of the
`interaction of beta and gamma particles with
`human tissue is proportionally related to the
`amount of administered dosage. The radiobio-
`logical effects of beta and gamma radiation
`may potentially be harmful at any age, if a very
`large dosage is administered, although typical
`PET dosage levels are within safety limits.
`However, dosage regularization may be particu-
`larly important for children and the fetus, which
`are considered highly radiosensitive [8, 27,
`28-31], primarily because their cells are divid-
`ing faster and, secondly, because they have
`longer life-time ahead to potentially develop
`long-term stochastic effects, such as carcino-
`genesis [8]. For instance, young children (5
`years old) exposed to radiation from an atomic
`bomb have 1.7-2.1 greater risk of developing
`cancer compared to young adults (20 years old)
`[32]. In addition, unlike dosage-radiobiological
`risk
`relationship described above, NECR-
`dosage curve is not linear, but instead exhibits
`a peak at moderate dosage levels, as it will be
`demonstrated later. Thus, very high dosages
`not only increase exposure, if applied repeat-
`edly, e.g. in longitudinal studies, but also are
`undesirable as they may in fact diminish statis-
`tical quality of the acquired PET data. On the
`other hand, extremely low dosage levels may as
`well impact quality, except if proportionally lon-
`ger PET acquisitions can be afforded, e.g. in the
`case of PET/MR acquisitions, to compensate
`for the low NECR [33]. Therefore, radiation
`exposure should be restricted to levels as low
`as reasonably achievable (ALARA principle) or
`avoided if not absolutely necessary for special
`radiosensitive population members such as
`children and pregnant women [15, 31, 34, 35].
`
`Thus, the ALARA concept encourages adminis-
`tration of reasonably low or moderate amounts
`of administered PET dosage after accounting
`for the available scan time and any other factor
`that could help further reduce exposure with-
`out affecting data quality. It essentially demon-
`strates both the need for dosage minimization
`as well as the importance of retaining sufficient
`or reasonable statistical quality. Therefore, any
`dosage
`regularization strategy, as
`those
`described in this review article, should follow
`the ALARA principles. Table 1 presents a
`collection of human population average
`exposure levels due to characteristic nuclear
`
`531
`
`Am J Nucl Med Mol Imaging 2015;5(5):527-547
`
`Petitioner GE Healthcare – Ex. 1037, p. 531
`
`

`

`Dosage optimization strategies in PET
`
`Table 1. Radiation exposure for characteristic medical exams and cosmic radiation levels
`Radiation exposure (mSv)
`Medical Imaging sources
`3-4
`FDG (185 MBq) PET scan
`7.0
`CT-chest
`25
`PET/CT (non-modified protocol)
`0.1
`Chest X-ray
`7.6
`PET scan (15 yrs old)-modified protocol
`5.9
`CT scan (15 yrs old)-modified protocol
`13.5
`PET/CT scan (15 yrs old)-modified protocol
`Exposure from PET and CT vary upon scan purpose and local protocols. Data collected from literature [2, 32, 36-38].
`
`Daily activities and occupations (Cosmic radiation)
`Flight: Montreal to London
`0.0478
`Dentistry
`0.06 (annual)
`Living at sea level
`0.24
`Average dose/person (UK)
`2.5 (annual)
`Aircrew
`4.5 (annual)
`Metal mines
`2.7 (annual)
`
`randoms are contaminating
`rements.
`
`the measu-
`
`Thus, an alternative acquisition scheme result-
`ing in similar total number of counts but
`acquired from a smaller amount of dosage and
`for longer time period may be more appropriate
`from a statistical and dosimetric point of view
`as it will be associated with a larger trues frac-
`tion and less radiation exposure for the patient
`and the personnel. On the other hand, pro-
`longed scan periods may not be clinically feasi-
`ble, given the high patient throughput require-
`ments in the PET clinic.
`
`NECR
`
`=
`
`true
`
`2
`
`true
`
`scatter
`
`random
`
`A suitable metric to quantify the overall statisti-
`cal usefulness of the total count rates by taking
`into account their synthesis is NECR [3, 10] and
`is defined as follows [9]:
`R
`+
`+
`aR
`R
`bR
`where Rtrue, Rscatter and Rrandom denote the true,
`scatter and random coincidences count rates,
`respectively. Also ‘α’ represents the occupied
`area in the FOV by the patient while ‘b’ depends
`on the method used to estimate random events
`[33]. As its name implies, NECR can be consid-
`ered as the equivalent trues count rate that
`would yield to the same level of statistical noise
`as the one currently present in the measured
`prompt counts [39].
`
`medicine exams (left column) and cosmic radi-
`ation (right column), as compiled from pub-
`lished reports [2, 32, 36-38]. Although the
`occupational dose limit for an adult is only 50
`mSv, the ALARA principles should always be fol-
`lowed in medical procedures for the maximum
`reasonable limitation of patient and personnel
`exposure.
`
`The importance of thenoise-equivalent count-
`ing rate (NECR) metric
`
`An important parameter when evaluating the
`performance of a PET system is the count rate
`as a function of the total activity present in the
`FOV because it can considerably affect the sta-
`tistical quality and SNR of projection data and
`IQ of reconstructed images for a given imaging
`protocol [3]. The inherent uncertainty in coinci-
`dence rate measurements is expressed with
`the presence of noise in the projection and
`image space. The Poisson properties of the
`counts distribution in PET measurements sug-
`gest lower percentage noise and enhanced
`SNR when higher numbers of true coincidence
`counts are acquired. Thus, studies have sug-
`gested increasing the amount of injected dos-
`age as an attempt to limit the presence of noise
`in the acquired PET data [3]. However, this
`strategy may have negative implications for
`both the data quality in the projection and
`image data as well as the patient. In particular,
`the administration of very large amounts of
`dosage is expected to i) considerably rise the
`number of randoms and the associated arti-
`facts, ii) trigger counting losses due to dead-
`time effect and iii) increase radiation exposure
`[13]. In other words, not only the total number
`of counts (prompts) but also their synthesis in
`trues, scatter and randoms is also important
`from a statistical point of view, as scatter and
`
`Random coincidences can be estimated by
`employing a delayed coincidence window (δ +
`ΔT) which is time-shifted relative to the stan-
`dard coincidence window (ΔT) [9]. The use of
`delayed window allows for the exclusive esti-
`mation of random events spatial distribution,
`thus providing an automated and practical
`method for online randoms subtraction from
`
`532
`
`Am J Nucl Med Mol Imaging 2015;5(5):527-547
`
`Petitioner GE Healthcare – Ex. 1037, p. 532
`
`

`

`Dosage optimization strategies in PET
`
`Figure 2. Random (sub-figure A), true (sub-figure B) and scatter (sub-figure C) coincidences counts as a function of
`injected dosage activity for six patients (A, B,…, F) of different weights (legend of sub-figure A). Obtained with permis-
`sion from Monte Carlo simulation of PET images for injection dose optimization/Jiri Boldys, Jiri Dvorak, Magdalena
`Skopalova and Otakar Belohlavek/ International Journal for Numerical Methods in Biomedical Engineering 2013;
`29: 988-999. Copyright © 2012 John Wiley & Sons, Ltd [45].
`
`the prompts distribution, the latter estimated
`from the original window [9]. However, random
`online subtraction can significantly increase
`the statistical noise in the data. On the other
`hand, estimation of scatter coincidences is
`possible by applying a scatter simulation algo-
`rithm on registered anatomical images, when
`the activity distribution is entirely within the
`scanner FOV [9]. The estimated scatter count
`profile is then subtracted from the prompts pro-
`jection profiles. Overall, the true coincidences
`rate can be estimated by Rtrue = Rprompt - Rscatter -
`Rrandom [10].
`NECR has been evaluated by many studies [10,
`14, 40] as a surrogate metric of statistical qual-
`ity of acquired projection data. The objective
`quantitative assessment of the statistical qual-
`ity of acquired PET raw data offered by the
`NECR metric could help towards a more effi-
`cient optimization of the administered dosage
`which,
`in
`turn, determines
`the
`trade-off
`between competing scanner and patient fac-
`tors. By modeling the relation between the indi-
`vidual components of NECR response (trues,
`scatter and randoms) and various patient- and
`scanner-related factors of PET studies, it is
`possible to predict the minimum administered
`dosage required to acquire sufficient noise
`equivalent counts within a clinically acceptable
`scan period [13].
`
`The detected coincidence counts at every line
`of response (LOR) bin in the raw data follow the
`Poisson distribution. Thus, the standard devia-
`tion (δ) of each estimated count rate is expect-
`ed to be equal to the square root of the mea-
`sured mean count rates N, i.e.
`, suppos-
`=v
`N
`ing the same activity distribution was measured
`
`multiple times. Then, the ratio of the standard
`deviation of counts to their mean, known as %
`statistical noise,
`can be derived by
`^
`h
`, where N represents the mean
`1 N
`100
`#
`counts in each LOR [41]. Moreover, NECR per
`pixel denotes the metric of NECR density
`(NECRD) [42] and is obtained by dividing NECR
`by the number of image pixels defining the
`attenuating volume of the scanned patient. On
`the other hand, the SNR of the projection data
`is defined as the ratio of the mean pixel value to
`
`the standard deviation, i.e. / NN
` and it
`=
`N
`is equivalent to the square root of NEC counts
`data equiv. to
`for a fixed acquisition time Δt (SNR2
`NEC = NECR × Δt) [10, 11, 43]. A recent study
`investigated the relationship between NEC and
`SNR2 in an experimental phantom set-up as
`well as in clinical PET scans and found satisfac-
`tory correlation between the two metrics in all
`phantom cases while, in the clinical cases, high
`correlation was observed for low and moderate
`body mass index (BMI) indices (< 28 kg/m2).
`The authors note that further studies are
`required to determine this relationship for
`patients of higher BMI indices [44].
`
`There are strong indications that NECR can be
`a suitable criterion for determining the optimal
`amount of administered dosage in a PET clini-
`cal study. Nevertheless, as explained above,
`NECR refers directly to the statistical quality
`(SNR2) of the projection data (sinogram) mea-
`surements only. Although the average quality of
`the reconstructed
`images
`is expected to
`increase with NECR for the same reconstruc-
`tion algorithm, image regions of different level
`of counts may be affected differently. Moreover,
`each iteration of various reconstruction algo-
`rithms may exercise a different impact in the
`
`533
`
`Am J Nucl Med Mol Imaging 2015;5(5):527-547
`
`Petitioner GE Healthcare – Ex. 1037, p. 533
`
`

`

`Dosage optimization strategies in PET
`
`final quality of the images for the same set of
`projection data. Thus, despite the usefulness
`of the NECR in quantifying the statistical quality
`of PET projection data, its value as a metric of
`quality of the images is limited and depends on
`a large set of reconstruction parameters. Thus,
`NECR may not be a 100% reliable indicato
`when the target is quality of a specific image
`ROI, as the choice of a reconstruction algorithm
`may considerably affect IQ to an extent that
`cannot be predicted by NECR alone [14].
`
`Noise-equivalent counting rate and injected
`dosage: The administration of amounts of activ-
`ity below or above the recommended optimal
`dosage levels can be problematic for various
`reasons. Figure 2 presents the effect of within
`FOV activity distributions on true, scatter and
`random coincidence events. Very large amounts
`of administered dosage may degrade SNR in
`projection data and quality of images due to
`the relatively higher increase rate of random
`(Figure 2A) compared to true (Figure 2B) and
`scatter (Figure 2C) coincidences [45, 46].
`
`This is attributed to the exponential relation-
`ship between randoms rate and activity, unlike
`true and scatter coincidence rates that are
`exhibiting an approximately linear dependence
`with activity. As a result, NECR will increase
`with dosage at low injected levels but then
`is expected to level-off or even drop as the dos-
`age becomes moderate o