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

Cross-validation study between the HRRT and the PET component of the SIGNA PET/MRI system with focus on neuroimaging

Background: The Siemens high-resolution research tomograph (HRRT - a dedicated brain PET scanner) is to this day one of the highest resolution PET scanners; thus, it can serve as useful benchmark when evaluating performance of newer scanners. Here, we report results from a cross-validation study between the HRRT and the whole-body GE SIGNA PET/MR focusing on brain imaging. Phantom data were acquired to determine recovery coefficients (RCs), % background variability (%BG), and image voxel noise (%). Cross-validation studies were performed with six healthy volunteers using [11C]DTBZ, [11C]raclopride, and [18F]FDG. Line profiles, regional time-activity curves, regional non-displaceable binding potentials (BPND) for [11C]DTBZ and [11C]raclopride scans, and radioactivity ratios for [18F]FDG scans were calculated and compared between the HRRT and the SIGNA PET/MR. Results: Phantom data showed that the PET/MR images reconstructed with an ordered subset expectation maximization (OSEM) algorithm with time-of-flight (TOF) and TOF + point spread function (PSF) + filter revealed similar RCs for the hot spheres compared to those obtained on the HRRT reconstructed with an ordinary Poisson-OSEM algorithm with PSF and PSF + filter. The PET/MR TOF + PSF reconstruction revealed the highest RCs for all hot spheres. Image voxel noise of the PET/MR system was significantly lower. Line profiles revealed excellent spatial agreement between the two systems. BPND values revealed variability of less than 10% for the [11C]DTBZ scans and 19% for [11C]raclopride (based on one subject only). Mean [18F]FDG ratios to pons showed less than 12% differences. Conclusions: These results demonstrated comparable performances of the two systems in terms of RCs with lower voxel-level noise (%) present in the PET/MR system. Comparison of in vivo human data confirmed the comparability of the two systems. The whole-body GE SIGNA PET/MR system is well suited for high-resolution brain imaging as no significant performance degradation was found compared to that of the reference standard HRRT.Science, Faculty ofOther UBCNon UBCPhysics and Astronomy, Department ofReviewedFacult

Standardization of Small Animal Imaging—Current Status and Future Prospects

The benefit of small animal imaging is directly linked to the validity and reliability of the collected data. If the data (regardless of the modality used) are not reproducible and/or reliable, then the outcome of the data is rather questionable. Therefore, standardization of the use of small animal imaging equipment, as well as of animal handling in general, is of paramount importance. In a recent paper, guidance for efficient small animal imaging quality control was offered and discussed, among others, the use of phantoms in setting up a quality control program (Osborne et al. 2016). The same phantoms can be used to standardize image quality parameters for multi-center studies or multi-scanners within center studies. In animal experiments, the additional complexity due to animal handling needs to be addressed to ensure standardized imaging procedures. In this review, we will address the current status of standardization in preclinical imaging, as well as potential benefits from increased levels of standardization

Assessment of murine brain tissue shrinkage caused by different histological fixatives using magnetic resonance and computed tomography imaging

Especially for neuroscience and the development of new biomarkers, a direct correlation between in vivo imaging and histology is essential. However, this comparison is hampered by deformation and shrinkage of tissue samples caused by fixation, dehydration and paraffin embedding. We used magnetic resonance (MR) imaging and computed tomography (CT) imaging to analyze the degree of shrinkage on murine brains for various fixatives. After in vivo imaging using 7 T MRI, animals were sacrificed and the brains were dissected and immediately placed in different fixatives, respectively: zinc-based fixative, neutral buffered formalin (NBF), paraformaldehyde (PFA), Bouin-Holland fixative and paraformaldehyde-lysine-periodate (PLP). The degree of shrinkage based on mouse brain volumes, radiodensity in Hounsfield units (HU), as well as non-linear deformations were obtained. The highest degree of shrinkage was observed for PLP (68.1%, P<0.001), followed by PFA (60.2%, P<0.001) and NBF (58.6%, P<0.001). The zinc-based fixative revealed a low shrinkage with only 33.5% (P<0.001). Compared to NBF, the zinc-based fixative shows a slightly higher degree of deformations, but is still more homogenous than PFA. Tissue shrinkage can be monitored non-invasively with CT and MR. Zinc-based fixative causes the smallest degree of brain shrinkage and only small deformations and is therefore recommended for in vivo ex vivo comparison studies

Checkpoint kinase Chk2 controls renal Cyp27b1 expression, calcitriol formation, and calcium-phosphate metabolism

Checkpoint kinase 2 (Chk2) is the main effector kinase of ataxia telangiectasia mutated (ATM) and responsible for cell cycle regulation. ATM signaling has been shown to upregulate interferon-regulating factor-1 (IRF-1), a transcription factor also expressed in the kidney. Calcitriol (1,25 (OH)2D3), a major regulator of mineral metabolism, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney. Since 25-hydroxyvitamin D 1α-hydroxylase expression is enhanced by IRF-1, the present study explored the role of Chk2 for calcitriol formation and mineral metabolism. Chk2-deficient mice (chk2 (-/-)) were compared to wild-type mice (chk2 (+/+)). Transcript levels of renal 25-hydroxyvitamin D 1α-hydroxylase, Chk2, and IRF-1 were determined by RT-PCR; Klotho expression by Western blotting; bone density by μCT analysis; serum or plasma 1,25 (OH)2D3, PTH, and C-terminal FGF23 concentrations by immunoassays; and serum, fecal, and urinary calcium and phosphate concentrations by photometry. The renal expression of IRF-1 and 25-hydroxyvitamin D 1α-hydroxylase as well as serum 1,25 (OH)2D3 and FGF23 levels were significantly lower in chk2 (-/-) mice compared to chk2 (+/+) mice. Plasma PTH was not different between the genotypes. Renal calcium and phosphate excretion were significantly higher in chk2 (-/-) mice than in chk2 (+/+) mice despite hypophosphatemia and normocalcemia. Bone density was not different between the genotypes. We conclude that Chk2 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression thereby impacting on calcium and phosphate metabolism

Data Curation for Preclinical and Clinical Multimodal Imaging Studies

Purpose: In biomedical research, imaging modalities help discover pathological mechanisms to develop and evaluate novel diagnostic and theranostic approaches. However, while standards for data storage in the clinical medical imaging field exist, data curation standards for biomedical research are yet to be established. This work aimed at developing a free secure file format for multimodal imaging studies, supporting common in vivo imaging modalities up to five dimensions as a step towards establishing data curation standards for biomedical research. Procedures: Images are compressed using lossless compression algorithm. Cryptographic hashes are computed on the compressed image slices. The hashes and compressions are computed in parallel, speeding up computations depending on the number of available cores. Then, the hashed images with digitally signed timestamps are cryptographically written to file. Fields in the structure, compressed slices, hashes, and timestamps are serialized for writing and reading from files. The C++ implementation is tested on multimodal data from six imaging sites, well-documented, and integrated into a preclinical image analysis software. Results: The format has been tested with several imaging modalities including fluorescence molecular tomography/x-ray computed tomography (CT), positron emission tomography (PET)/CT, single-photon emission computed tomography/CT, and PET/magnetic resonance imaging. To assess performance, we measured the compression rate, ratio, and time spent in compression. Additionally, the time and rate of writing and reading on a network drive were measured. Our findings demonstrate that we achieve close to 50 % reduction in storage space for μCT data. The parallelization speeds up the hash computations by a factor of 4. We achieve a compression rate of 137 MB/s for file of size 354 MB. Conclusions: The development of this file format is a step to abstract and curate common processes involved in preclinical and clinical multimodal imaging studies in a standardized way. This work also defines better interface between multimodal imaging modalities and analysis software.RST/Biomedical Imagin

Data Curation for Preclinical and Clinical Multimodal Imaging Studies

Purpose: In biomedical research, imaging modalities help discover pathological mechanisms to develop and evaluate novel diagnostic and theranostic approaches. However, while standards for data storage in the clinical medical imaging field exist, data curation standards for biomedical research are yet to be established. This work aimed at developing a free secure file format for multimodal imaging studies, supporting common in vivo imaging modalities up to five dimensions as a step towards establishing data curation standards for biomedical research. Procedures: Images are compressed using lossless compression algorithm. Cryptographic hashes are computed on the compressed image slices. The hashes and compressions are computed in parallel, speeding up computations depending on the number of available cores. Then, the hashed images with digitally signed timestamps are cryptographically written to file. Fields in the structure, compressed slices, hashes, and timestamps are serialized for writing and reading from files. The C++ implementation is tested on multimodal data from six imaging sites, well-documented, and integrated into a preclinical image analysis software. Results: The format has been tested with several imaging modalities including fluorescence molecular tomography/x-ray computed tomography (CT), positron emission tomography (PET)/CT, single-photon emission computed tomography/CT, and PET/magnetic resonance imaging. To assess performance, we measured the compression rate, ratio, and time spent in compression. Additionally, the time and rate of writing and reading on a network drive were measured. Our findings demonstrate that we achieve close to 50 % reduction in storage space for μCT data. The parallelization speeds up the hash computations by a factor of 4. We achieve a compression rate of 137 MB/s for file of size 354 MB. Conclusions: The development of this file format is a step to abstract and curate common processes involved in preclinical and clinical multimodal imaging studies in a standardized way. This work also defines better interface between multimodal imaging modalities and analysis software.RST/Biomedical Imagin