Understanding the importance of quality control and quality assurance in preclinical PET/CT imaging

The fundamental principle of experimental design is to ensure efficiency and efficacy of the performed experiments. Therefore, it behoves the researcher to gain knowledge of the technological equipment to be used. This should include an understanding of the instrument quality control and assurance requirements to avoid inadequate or spurious results due to instrumentation bias whilst improving reproducibility. Here, the important role of preclinical positron emission tomography/computed tomography and the scanner's required quality control and assurance is presented along with the suggested guidelines for quality control and assurance. There are a multitude of factors impeding the continuity and reproducibility of preclinical research data within a single laboratory as well as across laboratories. A more robust experimental design incorporating validation or accreditation of the scanner performance can reduce inconsistencies. Moreover, the well-being and welfare of the laboratory animals being imaged is prime justification for refining experimental designs to include verification of instrumentation quality control and assurance. Suboptimal scanner performance is not consistent with the 3R principle (Replacement, Reduction, and Refinement) and potentially subjects animals to unnecessary harm. Thus, quality assurance and control should be of paramount interest to any scientist conducting animal studies. For this reason, through this work, we intend to raise the awareness of researchers using PET/CT regarding quality control/quality assurance (QC/QA) guidelines and instil the importance of confirming that these are routinely followed. We introduce a basic understanding of the PET/CT scanner, present the purpose of QC/QA as well as provide evidence of imaging data biases caused by lack of QC/QA. This is shown through a review of the literature, QC/QA accepted standard protocols and our research. We also want to encourage researchers to have discussions with the PET/CT facilities manager and/or technicians to develop the optimal designed PET/CT experiment for obtaining their scientific objective. Additionally, this work provides an easy gateway to multiple resources not only for PET/CT knowledge but for guidelines and assistance in preclinical experimental design to enhance scientific integrity of the data and ensure animal welfare

Standardisation of preclinical PET/CT protocols across multiple research centres

Preclinical Positron Emission Tomography/Computed Tomography (PET/CT) is a well-established non-invasive imaging tool for studying disease development/progression, the development of novel radiotracers and pharmaceuticals for clinical applications. Over the last five years more than 8,200 preclinical studies using PET/CT were conducted. Despite this pivotal role, standardisation of preclinical PET/CT protocols, including CT absorbed dose guidelines, is essentially non-existent. Therefore, the first and second aims of this project were: (1) to quantitatively assess the variability of current preclinical PET and CT acquisition and reconstruction protocols in routine use across multiple centres and scanners; and (2) to propose optimized standardised acquisition and reconstruction PET/CT protocols for routine scanning procedures across all sites in a preclinical PET/CT laboratory. By assessing quantitative accuracy (known versus measured) and precision (reduced variability) of currently used routine protocols between five different sites/scanners (Bruker Albira, Mediso nanoPET/CT, Sedecal Super Argus, Siemens Inveon and Trifoil LabPET/CT), standard protocols were determined. Thereby, irrespective of scanner characteristics the least biased empirical quantitative and qualitative protocol results defined the standard protocol. In essence, neutralizing the manufacturers' difference, replacing scanner variability for scanner similarity to establish global standard protocols. The analysis of sites’ routine protocol results revealed significant quantitative differences between all five sites/scanners. Whereas the standard protocols put forth improved accuracy and precision across all sites. Additionally, the large disparity and measured amounts of CT absorbed ionising radiation amongst sites brought to light the lack of preclinical radiation guidelines and dose regulations. Unregulated CT radiation dose is of great concern. CT ionising radiation is known to have biological adverse effects. Thus, overexposure of radiation will potentially cause unnecessary animal suffering and confound research outcomes. Overall, the proposed standard CT protocol reduced radiation doses. The implementation of preclinical PET/CT standardised protocols, developed and tested in this project, will provide more robust, reliable and reproducible translational data sets for clinical applications. In accordance with the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) objectives, the refinement of PET/CT protocols and reduction of CT absorbed dose impacts animal welfare positively and potentially reduces the number of animals used. Reducing study variability in site and across sites through standardisation of protocols improves statistically significant results using less animals. For study specific imaging parameters in preclinical PET/CT rodents are commonly used to design the protocol. The third aim of this project strives to develop a tissue equivalent material (TEM) anthropomorphic rodent phantom for the replacement of animals when designing and optimizing varying in vivo rodent imaging protocols. Using a TEM phantom reduces potential biological experimental variability caused by the animals and increases reproducibility of findings. To address this aim, twenty-four commercially available 3D printing materials were X-rayed for the evaluation Hounsfield units (HU). A comparison of calculated 3D material attenuation coefficients and accepted tissue attenuation coefficient was also done. CT images were acquired using four CT protocols and the developed standard CT protocol. Based on measured material HUs compared to accepted tissue/organ HU values, four materials were chosen for testing and further evaluation in a 3D printed phantom prototype was undertaken. In order to obtain the anatomical features of the rodent a CT acquisition of a scheduled 1 rodent was acquired. The CT images were used for the 3D printing design. A 3D printed (TEM) anthropomorphic rodent phantoms was printed and tested. Measured HU analysis of the phantom TEM materials shows promise as a replacement strategy. This imaging protocol optimisation approach is also in line with the NC3Rs objective of replacing and/or avoiding the use animals

Cherenkov luminescence measurements with digital silicon photomultipliers: a feasibility study.

BackgroundA feasibility study was done to assess the capability of digital silicon photomultipliers to measure the Cherenkov luminescence emitted by a β source. Cherenkov luminescence imaging (CLI) is possible with a charge coupled device (CCD) based technology, but a stand-alone technique for quantitative activity measurements based on Cherenkov luminescence has not yet been developed. Silicon photomultipliers (SiPMs) are photon counting devices with a fast impulse response and can potentially be used to quantify β-emitting radiotracer distributions by CLI.MethodsIn this study, a Philips digital photon counting (PDPC) silicon photomultiplier detector was evaluated for measuring Cherenkov luminescence. The PDPC detector is a matrix of avalanche photodiodes, which were read one at a time in a dark count map (DCM) measurement mode (much like a CCD). This reduces the device active area but allows the information from a single avalanche photodiode to be preserved, which is not possible with analog SiPMs. An algorithm to reject the noisiest photodiodes and to correct the measured count rate for the dark current was developed.ResultsThe results show that, in DCM mode and at (10-13) °C, the PDPC has a dynamic response to different levels of Cherenkov luminescence emitted by a β source and transmitted through an opaque medium. This suggests the potential for this approach to provide quantitative activity measurements. Interestingly, the potential use of the PDPC in DCM mode for direct imaging of Cherenkov luminescence, as a opposed to a scalar measurement device, was also apparent.ConclusionsWe showed that a PDPC tile in DCM mode is able to detect and image a β source through its Cherenkov radiation emission. The detector's dynamic response to different levels of radiation suggests its potential quantitative capabilities, and the DCM mode allows imaging with a better spatial resolution than the conventional event-triggered mode. Finally, the same acquisition procedure and data processing could be employed also for other low light levels applications, such as bioluminescence

Editorial: Small animal imaging: Technological and methodological advances to improve the translational power

Radiolog

Characterisation of an atherosclerotic micro-calcification model using ApoE-/- mice and PET/CT

Intraplaque calcification is a prominent feature of advanced atherosclerotic plaque development. Current clinical evidence suggests that the size of calcium deposit may confer different effects on plaque stability [1], [2], [3]. Macro-calcified deposits (CT detected) are thought to confer plaque stability whereas micro-calcification ([18F]NaF PET detected) are thought to be a feature of high-risk ‘vulnerable’ plaques which are prone to rupture. Following on from the emerging role of micro-calcification in high risk plaques within the clinic [4], there is now an urgent need for preclinical atherosclerotic models with this feature to gain mechanistic insights and assess the impact of calcification-targeted therapies. Using a combination of invasive and ex vivo methods, ApoE−/− mice placed on an atherogenic diet have been shown to develop intraplaque calcification [5]. Additionally, [18F]NaF PET/CT has been used to assess the impact of exercise on calcification in ApoE−/− mice on a western diet [6]. In this study, we set out to determine if [18F]NaF PET/CT could be used to non-invasively detect and quantify micro-calficiation in the ApoE−/− high cholesterol diet (HCD) mouse model, and examine the temporal nature of this process

Community Survey Results Show that Standardisation of Preclinical Imaging Techniques Remains a Challenge

Abstract Purpose To support acquisition of accurate, reproducible and high-quality preclinical imaging data, various standardisation resources have been developed over the years. However, it is unclear the impact of those efforts in current preclinical imaging practices. To better understand the status quo in the field of preclinical imaging standardisation, the STANDARD group of the European Society of Molecular Imaging (ESMI) put together a community survey and a forum for discussion at the European Molecular Imaging Meeting (EMIM) 2022. This paper reports on the results from the STANDARD survey and the forum discussions that took place at EMIM2022. Procedures The survey was delivered to the community by the ESMI office and was promoted through the Society channels, email lists and webpages. The survey contained seven sections organised as generic questions and imaging modality-specific questions. The generic questions focused on issues regarding data acquisition, data processing, data storage, publishing and community awareness of international guidelines for animal research. Specific questions on practices in optical imaging, PET, CT, SPECT, MRI and ultrasound were further included. Results Data from the STANDARD survey showed that 47% of survey participants do not have or do not know if they have QC/QA guidelines at their institutes. Additionally, a large variability exists in the ways data are acquired, processed and reported regarding general aspects as well as modality-specific aspects. Moreover, there is limited awareness of the existence of international guidelines on preclinical (imaging) research practices. Conclusions Standardisation of preclinical imaging techniques remains a challenge and hinders the transformative potential of preclinical imaging to augment biomedical research pipelines by serving as an easy vehicle for translation of research findings to the clinic. Data collected in this project show that there is a need to promote and disseminate already available tools to standardise preclinical imaging practices. </jats:sec

PET/CT TECHNOLOGY IN ADULT ZEBRAFISH: A PILOT STUDY TOWARD LIVE LONGITUDIANAL IMAGING

Decades of research have confirmed the beneficial and advantageous use of zebrafish (Danio rerio) as a model of human disease in biomedical studies. Not only are 71% of human genes shared with the zebrafish many of these genes are linked to human diseases. Currently, numerous transgenic and mutant genetic zebrafish lines are now widely available for use in research. Furthermore, zebrafish are relatively inexpensive to maintain compared to rodents. However, a limiting factor to fully utilising adult zebrafish in research is not the fish but the technological imaging tools available. In order to increase the utilisation of adult zebrafish, which are not naturally transparent, requires new imaging approaches. Therefore, this feasibility study: (1) presents an innovative designed PET/CT adult zebrafish imaging platform, capable of maintaining normal aquatic physiology during scanning; (2) assesses the practical aspects of adult zebrafish imaging; and (3) set basic procedural guidelines for zebrafish imaging during a PET/CT acquisition.Methods: With computer aided design (CAD) software an imaging platform was developed for 3D printing. A 3D printed zebrafish model was created from a CT acquisition of a zebrafish using the CAD software. This model and subsequently euthanised zebrafish were imaged post-injection using different concentrations of the radiotracer [18F]FDG with CT contrast.Results: PET/CT imaging was successful, revealing levels as low as 0.01 MBq could be detected in the fish. In the zebrafish imaging post-injection distribution of the radiotracer was observed away from the injection site as well as tissue uptake. Potential preliminary husbandry and welfare guidelines for the fish during and after PET/CT imaging were determined.Conclusion: Using PET/CT for adult zebrafish imaging as a viable non-invasive technological tool is feasible. Adult zebrafish PET/CT imaging has the potential to be a key imaging technique offering the possibilities of enhanced biomedical understanding and new translational data sets

CT Image datasets for highdose 16A2XXX and 16A3XXX

High dose microCT does not contribute towards improved microPET/CT image quantitative accuracy and can limit longitudinal scanning of small animals ABSTRACT Obtaining accurate quantitative measurements in preclinical Positron Emission Tomography/Computed Tomography (PET/CT) imaging is of paramount importance in biomedical research and helps supporting efficient translation of preclinical results to the clinic. The purpose of this study was two-fold: (1) to investigate the effects of different CT acquisition protocols on PET/CT image quality and data quantification; and (2) to evaluate the absorbed dose associated with varying CT parameters. Methods: An air/water quality control CT phantom, tissue equivalent material phantom, an in-house 3D printed phantom and an image quality PET/CT phantom were imaged using a Mediso nanoPET/CT scanner. Collected data was analyzed using PMOD software, VivoQuant software and National Electric Manufactures Association (NEMA) software implemented by Mediso. Measured Hounsfield Unit (HU) in collected CT images were compared to the known HU values and image noise was quantified. PET recovery coefficients (RC), uniformity and quantitative bias were also measured. Results: Only less than 2% and 1% of CT acquisition protocols yielded water HU values of less than -80 and air HU values of less than -840, respectively. Four out of eleven CT protocols resulted in more than 100 mGy absorbed dose. Different CT protocols did not impact PET uniformity and RC, and resulted in less than 4% overall bias relative to expected radioactive concentration. Conclusion: Preclinical CT protocols with increased exposure times can result in high absorbed doses to the small animals. These should be avoided, as they do not contributed towards improved microPET/CT image quantitative accuracy and could limit longitudinal scanning of small animals.McDougald, Wendy. (2019). CT Image datasets for highdose 16A2XXX and 16A3XXX, [image]. University of Edinburgh. Medical School. Centre for Cardiovascular Science. https://doi.org/10.7488/ds/2727

CT Image datasets for highdose 16A0XXX and 16A1XXX

High dose microCT does not contribute towards improved microPET/CT image quantitative accuracy and can limit longitudinal scanning of small animals ABSTRACT Obtaining accurate quantitative measurements in preclinical Positron Emission Tomography/Computed Tomography (PET/CT) imaging is of paramount importance in biomedical research and helps supporting efficient translation of preclinical results to the clinic. The purpose of this study was two-fold: (1) to investigate the effects of different CT acquisition protocols on PET/CT image quality and data quantification; and (2) to evaluate the absorbed dose associated with varying CT parameters. Methods: An air/water quality control CT phantom, tissue equivalent material phantom, an in-house 3D printed phantom and an image quality PET/CT phantom were imaged using a Mediso nanoPET/CT scanner. Collected data was analyzed using PMOD software, VivoQuant software and National Electric Manufactures Association (NEMA) software implemented by Mediso. Measured Hounsfield Unit (HU) in collected CT images were compared to the known HU values and image noise was quantified. PET recovery coefficients (RC), uniformity and quantitative bias were also measured. Results: Only less than 2% and 1% of CT acquisition protocols yielded water HU values of less than -80 and air HU values of less than -840, respectively. Four out of eleven CT protocols resulted in more than 100 mGy absorbed dose. Different CT protocols did not impact PET uniformity and RC, and resulted in less than 4% overall bias relative to expected radioactive concentration. Conclusion: Preclinical CT protocols with increased exposure times can result in high absorbed doses to the small animals. These should be avoided, as they do not contributed towards improved microPET/CT image quantitative accuracy and could limit longitudinal scanning of small animals.McDougald, Wendy. (2019). CT Image datasets for highdose 16A0XXX and 16A1XXX, [image]. University of Edinburgh. Medical School. Centre for Cardiovascular Science. https://doi.org/10.7488/ds/2726