Mapping 18F-FDG Kinetics Together with Patient-Specific Bootstrap Assessment of Uncertainties: An Illustration with Data from a PET/CT Scanner with a Long Axial Field of View.

The purpose of this study was to examine a nonparametric approach to mapping kinetic parameters and their uncertainties with data from the emerging generation of dynamic whole-body PET/CT scanners. Methods: Dynamic PET 18F-FDG data from a set of 24 cancer patients studied on a long-axial-field-of-view PET/CT scanner were considered. Kinetics were mapped using a nonparametric residue mapping (NPRM) technique. Uncertainties were evaluated using an image-based bootstrapping methodology. Kinetics and bootstrap-derived uncertainties are reported for voxels, maximum-intensity projections, and volumes of interest (VOIs) corresponding to several key organs and lesions. Comparisons between NPRM and standard 2-compartment (2C) modeling of VOI kinetics are carefully examined. Results: NPRM-generated kinetic maps were of good quality and well aligned with vascular and metabolic 18F-FDG patterns, reasonable for the range of VOIs considered. On a single 3.2-GHz processor, the specification of the bootstrapping model took 140 min; individual bootstrap replicates required 80 min each. VOI time-course data were much more accurately represented, particularly in the early time course, by NPRM than by 2C modeling constructs, and improvements in fit were statistically highly significant. Although 18F-FDG flux values evaluated by NPRM and 2C modeling were generally similar, significant deviations between vascular blood and distribution volume estimates were found. The bootstrap enables the assessment of quite complex summaries of mapped kinetics. This is illustrated with maximum-intensity maps of kinetics and their uncertainties. Conclusion: NPRM kinetics combined with image-domain bootstrapping is practical with large whole-body dynamic 18F-FDG datasets. The information provided by bootstrapping could support more sophisticated uses of PET biomarkers used in clinical decision-making for the individual patient.

Quantitation of dynamic total-body PET imaging: recent developments and future perspectives.

BACKGROUND: Positron emission tomography (PET) scanning is an important diagnostic imaging technique used in disease diagnosis, therapy planning, treatment monitoring, and medical research. The standardized uptake value (SUV) obtained at a single time frame has been widely employed in clinical practice. Well beyond this simple static measure, more detailed metabolic information can be recovered from dynamic PET scans, followed by the recovery of arterial input function and application of appropriate tracer kinetic models. Many efforts have been devoted to the development of quantitative techniques over the last couple of decades. CHALLENGES: The advent of new-generation total-body PET scanners characterized by ultra-high sensitivity and long axial field of view, i.e., uEXPLORER (United Imaging Healthcare), PennPET Explorer (University of Pennsylvania), and Biograph Vision Quadra (Siemens Healthineers), further stimulates valuable inspiration to derive kinetics for multiple organs simultaneously. But some emerging issues also need to be addressed, e.g., the large-scale data size and organ-specific physiology. The direct implementation of classical methods for total-body PET imaging without proper validation may lead to less accurate results. CONCLUSIONS: In this contribution, the published dynamic total-body PET datasets are outlined, and several challenges/opportunities for quantitation of such types of studies are presented. An overview of the basic equation, calculation of input function (based on blood sampling, image, population or mathematical model), and kinetic analysis encompassing parametric (compartmental model, graphical plot and spectral analysis) and non-parametric (B-spline and piece-wise basis elements) approaches is provided. The discussion mainly focuses on the feasibilities, recent developments, and future perspectives of these methodologies for a diverse-tissue environment.

Accurate total-body Ki parametric imaging with shortened dynamic 18 F-FDG PET scan durations via effective data processing.

BACKGROUND: Total-body dynamic positron emission tomography (dPET) imaging using 18 F-fluorodeoxyglucose (18 F-FDG) has received widespread attention in clinical oncology. However, the conventionally required scan duration of approximately 1 h seriously limits the application and promotion of this imaging technique. In this study, we investigated the possibility and feasibility of shortening the total-body dynamic scan duration to 30 min post-injection (PI) with the help of a novel Patlak data processing algorithm for accurate Ki estimations of tumor lesions. METHODS: Total-body dPET images acquired by uEXPLORER (United Imaging Healthcare Inc.) using 18 F-FDG of 15 patients with different tumor types were analyzed in this study. Dynamic images were reconstructed into 25 frames with a specific temporal dividing protocol for the scan data acquired 1 h PI. Patlak analysis-based Ki parametric imaging was conducted based on the imaging data corresponding to the first 30 min PI, during which a Patlak data processing method based on cubic Hermite interpolation was applied. The resultant Ki images acquired by 30 min dynamic PET data and the standard 1 h Ki images were compared in terms of visual imaging effect, region signal-to-noise ratio, and Ki estimation accuracy to evaluate the performance of the proposed Ki imaging method with a shortened scan duration. RESULTS: With the help of Patlak data processing, acceptable Ki parametric images were obtained from dynamic PET data acquired with a scan duration of 30 min PI. Compared with Ki images obtained from unprocessed Patlak data, the resulting images from the proposed method performed better in terms of noise reduction. Moreover, Bland-Altman plot and Pearson correlation coefficient analysis showed that that 30 min Ki images obtained from the processed Patlak data had higher accuracy for tumor lesions. CONCLUSION: Satisfactory Ki parametric images with high tumor accuracy can be acquired from dynamic imaging data corresponding to the first 30 min PI. Patlak data processing can help achieve higher Ki imaging quality and higher accuracy regarding tumor lesion Ki values. Clinically, it is possible to shorten the dynamic scan duration of 18 F-FDG PET to 30 min to acquire an accurate tumor Ki and further effective tumor detection with uEXPLORER scanners.

Identifying the individual metabolic abnormities from a systemic perspective using whole-body PET imaging.

INTRODUCTION: Distinct physiological states arise from complex interactions among the various organs present in the human body. PET is a non-invasive modality with numerous successful applications in oncology, neurology, and cardiology. However, while PET imaging has been applied extensively in detecting focal lesions or diseases, its potential in detecting systemic abnormalities is seldom explored, mostly because total-body imaging was not possible until recently. METHODS: In this context, the present study proposes a framework capable of constructing an individual metabolic abnormality network using a subject's whole-body 18F-FDG SUV image and a normal control database. The developed framework was evaluated in the patients with lung cancer, the one discharged after suffering from Covid-19 disease, and the one that had gastrointestinal bleeding with the underlying cause unknown. RESULTS: The framework could successfully capture the deviation of these patients from healthy subjects at the level of both system and organ. The strength of the altered network edges revealed the abnormal metabolic connection between organs. The overall deviation of the network nodes was observed to be highly correlated to the organ SUV measures. Therefore, the molecular connectivity of glucose metabolism was characterized at a single subject level. CONCLUSION: The proposed framework represents a significant step toward the use of PET imaging for identifying metabolic dysfunction from a systemic perspective. A better understanding of the underlying biological mechanisms and the physiological interpretation of the interregional connections identified in the present study warrant further research.

Total-body parametric imaging using the Patlak model: Feasibility of reduced scan time.

PURPOSE: This study explored the feasibility of reducing the scan time of Patlak parametric imaging on the uEXPLORER. METHODS: A total of 65 patients (27 females and 38 males, age 56.1 ± 10.4) were recruited in this study. 18F fluorodeoxyglucose was injected, and its dose was adjusted by body weight (4.07 MBq/kg). Total-body dynamic scanning was performed on the uEXPLORER total-body Positron emission tomography/computed tomography (CT) scanner with a total scan time of 60 min from the injection. The image derived input function (IDIF) was obtained from the aortic arch. The voxelwise Patlak analysis was applied to generate the Ki images designated as GIDIF with different acquisition times (20-60, 30-60, 40-60, and 44-60 min). The population-based input function (PBIF) was constructed from the mean value of the IDIF from the population, and Ki images designated as GPBIF were generated using the PBIF. Nonlocalmeans (NLM) denoising was applied to the generated images to get two extra groups of (NLM-designated) images: GIDIF+NLM and GPBIF+NLM . Two radiologists evaluated the overall image quality, noise, and lesion detectability of the Ki images from different groups. The 20-60 min scans in GIDIF were selected as the gold standard for each patient. We determined that image quality is at sufficient level if all the lesions can be recognized and meet the clinical criteria. Ki values in muscle and lesion were compared across different groups to evaluate the quantitative accuracy. RESULTS: The overall image quality, image noise, and lesion conspicuity were significantly better in long time series than short time series in all four groups (all p < 0.001). The Ki images in the GIDIF and GPBIF groups generated from 30-min scans showed diagnostic value equivalent to the 40-min scans of GIDIF . While the image quality of the 16-min scans was poor, all lesions could still be detected. No significant difference was found between Ki values estimated with GIDIF and GPBIF in muscle and lesion regions (all p > 0.5). After applying the NLM filter, the coefficient of variation could be reduced on the order of (1%, 15%, 19%, and 37%) and (110%, 125%, 94%, and 69%) with four acquisition time schemes for lesion and muscle. The reduction percentage did not have a substantial difference in IDIF and PBIF group. The Ki images in the GIDIF+NLM and GPBIF+NLM groups generated from the 20-min acquisitions showed acceptable quality. All lesions could be found on the NLM processed images of the 16-min scans. No significant difference was found between Ki values produced with GIDIF+NLM and GPBIF+NLM in muscle and lesion regions(all p > 0.7). CONCLUSIONS: The Ki images generated by the PBIF-based Patlak model using a 20-min dynamic scan with the NLM filter achieved a similar diagnostic efficiency to images with GIDIF from 40-min dynamic data, and there is no significant difference between Ki images generated using IDIF or PBIF (p > 0.5).

Parametric image generation with the uEXPLORER total-body PET/CT system through deep learning.

PURPOSE: Total-body dynamic positron emission tomography/computed tomography (PET/CT) provides much sensitivity for clinical imaging and research, bringing new opportunities and challenges regarding the generation of total-body parametric images. This study investigated parametric [Formula: see text] images directly generated from static PET images without an image-derived input function on a 2-m total-body PET/CT scanner (uEXPLORER) using a deep learning model to significantly reduce the dynamic scanning time and improve patient comfort. METHODS: [Formula: see text]F-Fluorodeoxyglucose ([Formula: see text]F-FDG) 2-m total-body PET/CT image pairs were acquired for 200 patients (scanned once) with two protocols: one parametric PET image (60 min, 0[Formula: see text]60 min) and one static PET image (10 min, range of 50[Formula: see text]60 min). A deep learning model was implemented to predict parametric [Formula: see text] images from the static PET images. Evaluation metrics, including the peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM), and normalized mean square error (NMSE), were calculated for a 10-fold cross-validation assessment. Moreover, image quality was assessed by two nuclear medicine physicians in terms of clinical readings. RESULTS: The synthetic parametric PET images were qualitatively and quantitatively consistent with the reference images. In particular, the global mean SSIM between the synthetic and reference parametric [Formula: see text] images exceeded 0.9 across all test patients. On the other hand, the overall subjective quality of the synthetic parametric PET images was 4.00 ± 0.45 (the highest possible rating is 5) according to the two expert nuclear medicine physicians. CONCLUSION: The findings illustrated the feasibility of the proposed technique and its potential to reduce the required scanning duration for 2-m total-body dynamic PET/CT systems. Moreover, this study explored the potential of direct parametric image generation with uEXPLORER. Deep learning technologies may output high-quality synthetic parametric images, and the validation of clinical applications and the interpretability of network models still need further research in future works.

Tracer-specific reference tissues selection improves detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes in Alzheimer's disease.

This study sought to identify a reference tissue-based quantification approach for improving the statistical power in detecting changes in brain glucose metabolism, amyloid, and tau deposition in Alzheimer's disease studies. A total of 794, 906, and 903 scans were included for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir, respectively. Positron emission tomography (PET) and T1-weighted images of participants were collected from the Alzheimer's disease Neuroimaging Initiative database, followed by partial volume correction. The standardized uptake value ratios (SUVRs) calculated from the cerebellum gray matter, centrum semiovale, and pons were evaluated at both region of interest (ROI) and voxelwise levels. The statistical power of reference tissues in detecting longitudinal SUVR changes was assessed via paired t-test. In cross-sectional analysis, the impact of reference tissue-based SUVR differences between cognitively normal and cognitively impaired groups was evaluated by effect sizes Cohen's d and two sample t-test adjusted by age, sex, and education levels. The average ROI t values of pons were 86.62 and 38.40% higher than that of centrum semiovale and cerebellum gray matter in detecting glucose metabolism decreases, while the centrum semiovale reference tissue-based SUVR provided higher t values for the detection of amyloid and tau deposition increases. The three reference tissues generated comparable d images for 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir and comparable t maps for 18 F-florbetapir and 18 F-flortaucipir, but pons-based t map showed superior performance in 18 F-FDG. In conclusion, the tracer-specific reference tissue improved the detection of 18 F-FDG, 18 F-florbetapir, and 18 F-flortaucipir PET SUVR changes, which helps the early diagnosis, monitoring of disease progression, and therapeutic response in Alzheimer's disease.

A Generalized Linear modeling approach to bootstrapping multi-frame PET image data.

PET imaging is an important diagnostic tool for management of patients with cancer and other diseases. Medical decisions based on quantitative PET information could potentially benefit from the availability of tools for evaluation of associated uncertainties. Raw PET data can be viewed as a sample from an inhomogeneous Poisson process so there is the possibility to directly apply bootstrapping to raw projection-domain list-mode data. Unfortunately this is computationally impractical, particularly if data reconstruction is iterative or the acquisition protocol is dynamic. We develop a flexible statistical linear model analysis to be used with multi-frame PET image data to create valid bootstrap samples. The technique is illustrated using data from dynamic PET studies with fluoro-deoxyglucose (FDG) and fluoro-thymidine (FLT) in brain and breast cancer patients. As is often the case with dynamic PET studies, data have been archived without raw list-mode information. Using the bootstrapping technique maps of kinetic parameters and associated uncertainties are obtained. The quantitative performance of the approach is assessed by simulation. The proposed image-domain bootstrap is found to substantially match the projection-domain alternative. Analysis of results points to a close relation between relative uncertainty in voxel-level kinetic parameters and local reconstruction error. This is consistent with statistical theory.

Quantitation of multiple injection dynamic PET scans: an investigation of the benefits of pooling data from separate scans when mapping kinetics.

Multiple injection dynamic positron emission tomography (PET) scanning is used in the clinical management of certain groups of patients and in medical research. The analysis of these studies can be approached in two ways: (i) separate analysis of data from individual tracer injections, or (ii), concatenate/pool data from separate injections and carry out a combined analysis. The simplicity of separate analysis has some practical appeal but may not be statistically efficient. We use a linear model framework associated with a kinetic mapping scheme to develop a simplified theoretical understanding of separate and combined analysis. The theoretical framework is explored numerically using both 1D and 2D simulation models. These studies are motivated by the breast cancer flow-metabolism mismatch studies involving15O-water (H2O) and18F-Fluorodeoxyglucose (FDG) and repeat15O-H2O injections used in brain activation investigations. Numerical results are found to be substantially in line with the simple theoretical analysis: mean square error characteristics of alternative methods are well described by factors involving the local voxel-level resolution of the imaging data, the relative activities of the individual scans and the number of separate injections involved. While voxel-level resolution has dependence on scan dose, after adjustment for this effect, the impact of a combined analysis is understood in simple terms associated with the linear model used for kinetic mapping. This is true for both data reconstructed by direct filtered backprojection or iterative maximum likelihood. The proposed analysis has potential to be applied to the emerging long axial field-of-view PET scanners.

Reproducibility of Methods to Detect Differentially Expressed Genes from Single-Cell RNA Sequencing.

Detection of differentially expressed genes is a common task in single-cell RNA-seq (scRNA-seq) studies. Various methods based on both bulk-cell and single-cell approaches are in current use. Due to the unique distributional characteristics of single-cell data, it is important to compare these methods with rigorous statistical assessments. In this study, we assess the reproducibility of 9 tools for differential expression analysis in scRNA-seq data. These tools include four methods originally designed for scRNA-seq data, three popular methods originally developed for bulk-cell RNA-seq data but have been applied in scRNA-seq analysis, and two general statistical tests. Instead of comparing the performance across all genes, we compare the methods in terms of the rediscovery rates (RDRs) of top-ranked genes, separately for highly and lowly expressed genes. Three real and one simulated scRNA-seq data sets are used for the comparisons. The results indicate that some widely used methods, such as edgeR and monocle, have worse RDR performances compared to the other methods, especially for the top-ranked genes. For highly expressed genes, many bulk-cell-based methods can perform similarly to the methods designed for scRNA-seq data. But for the lowly expressed genes performance varies substantially; edgeR and monocle are too liberal and have poor control of false positives, while DESeq2 is too conservative and consequently loses sensitivity compared to the other methods. BPSC, Limma, DEsingle, MAST, t-test and Wilcoxon have similar performances in the real data sets. Overall, the scRNA-seq based method BPSC performs well against the other methods, particularly when there is a sufficient number of cells.