Assessing transcriptomic heterogeneity of single-cell RNASeq data by bulk-level gene expression data.

BACKGROUND: Single-cell RNA sequencing (sc-RNASeq) data illuminate transcriptomic heterogeneity but also possess a high level of noise, abundant missing entries and sometimes inadequate or no cell type annotations at all. Bulk-level gene expression data lack direct information of cell population composition but are more robust and complete and often better annotated. We propose a modeling framework to integrate bulk-level and single-cell RNASeq data to address the deficiencies and leverage the mutual strengths of each type of data and enable a more comprehensive inference of their transcriptomic heterogeneity. Contrary to the standard approaches of factorizing the bulk-level data with one algorithm and (for some methods) treating single-cell RNASeq data as references to decompose bulk-level data, we employed multiple deconvolution algorithms to factorize the bulk-level data, constructed the probabilistic graphical models of cell-level gene expressions from the decomposition outcomes, and compared the log-likelihood scores of these models in single-cell data. We term this framework backward deconvolution as inference operates from coarse-grained bulk-level data to fine-grained single-cell data. As the abundant missing entries in sc-RNASeq data have a significant effect on log-likelihood scores, we also developed a criterion for inclusion or exclusion of zero entries in log-likelihood score computation. RESULTS: We selected nine deconvolution algorithms and validated backward deconvolution in five datasets. In the in-silico mixtures of mouse sc-RNASeq data, the log-likelihood scores of the deconvolution algorithms were strongly anticorrelated with their errors of mixture coefficients and cell type specific gene expression signatures. In the true bulk-level mouse data, the sample mixture coefficients were unknown but the log-likelihood scores were strongly correlated with accuracy rates of inferred cell types. In the data of autism spectrum disorder (ASD) and normal controls, we found that ASD brains possessed higher fractions of astrocytes and lower fractions of NRGN-expressing neurons than normal controls. In datasets of breast cancer and low-grade gliomas (LGG), we compared the log-likelihood scores of three simple hypotheses about the gene expression patterns of the cell types underlying the tumor subtypes. The model that tumors of each subtype were dominated by one cell type persistently outperformed an alternative model that each cell type had elevated expression in one gene group and tumors were mixtures of those cell types. Superiority of the former model is also supported by comparing the real breast cancer sc-RNASeq clusters with those generated by simulated sc-RNASeq data. CONCLUSIONS: The results indicate that backward deconvolution serves as a sensible model selection tool for deconvolution algorithms and facilitates discerning hypotheses about cell type compositions underlying heterogeneous specimens such as tumors.

ASSESSING BODY DOSE RATE CONSTANT AND EFFECTIVE BODY ABSORPTION FACTOR IN TAIWANESE REFERENCE PHANTOMS.

The self-attenuation of a patient's body is an important factor in nuclear medicine for designing radiation shielding. Taiwanese reference man (TRM) and Taiwanese reference woman (TRW) were constructed to simulate the body dose rate constant and the effective body absorption factor for 18F-FDG, 131I-NaI and 99mTc-MIBI using the Monte Carlo technique. For TRM, the maximum body dose rate constants for 18F-FDG, 131I-NaI and 99mTc-MIBI were 1.26 × 10-1, 4.89 × 10-2 and 1.76 × 10-2 mSv-m2/GBq-h, respectively, at heights of 110, 110 and 100 cm. For TRW, the results were 1.23 × 10-1, 4.75 × 10-2 and 1.68 × 10-2 mSv-m2/GBq-h at heights of 100, 100 and 90 cm. The effective body absorption factors were 32.6, 36.7 and 46.2% for TRM and 34.2, 38.5 and 48.6% for TRW. Regional reference phantoms along with the derived body dose rate constant and effective body absorption factor should be used for determining regulatory secondary standards in nuclear medicine.

Meta-analysis of the effectiveness of heparin in suppressing physiological myocardial FDG uptake in PET/CT.

BACKGROUND: The present meta-analysis aims to investigate the effectiveness of heparin administration in suppressing physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/computed tomography (CT), as its role in this regard has not been well investigated. METHODS: PRISMA guidelines were used to interrogate the PubMed, Embase, Cochrane library, Web of Knowledge, and www.clinicaltrail.gov databases from the earliest records to March 2023. The final analysis included five randomized controlled trials (RCTs). Meta-analysis was conducted to compare the effectiveness of unfractionated heparin (UFH) administration versus non-UFH administration, and subgroup analysis based on fixed and variable fasting durations was conducted. Effect sizes were pooled using a random-effects model, and the pooled odds ratios (ORs) were calculated. RESULTS: Five eligible RCTs with a total of 910 patients (550 with heparin, 360 without heparin) were included. The forest plot analysis initially indicated no significant difference in the suppression of myocardial FDG uptake between the UFH and non-UFH groups (OR 2.279, 95% CI 0.593 to 8.755, p = 0.23), with a high degree of statistical heterogeneity (I2 = 91.16%). Further subgroup analysis showed that the fixed fasting duration group with UFH administration had statistically significant suppression of myocardial FDG uptake (OR 4.452, 95% CI 1.221 to 16.233, p = 0.024), while the varying fasting duration group did not show a significant effect. CONCLUSIONS: According to the findings of our meta-analysis, we suggest that intravenous administration of UFH can be considered as a supplementary approach to suppress myocardial FDG uptake.

Diagnosis of Osteoporosis by Quantifying Volumetric Bone Mineral Density of Lumbar Vertebrae Using Abdominal CT Images and Two-Compartment Model.

With the aging population, osteoporosis has become an important public health issue. The purpose of this study was to establish a two-compartment model (TCM) to quantify the volumetric bone mineral density (vBMD) of the lumbar spine using abdominal computed tomography (CT) images. The TCM approach uses water as the bone marrow equivalent and K2HPO4 solution as the cortical bone equivalent. A phantom study was performed to evaluate the accuracy of vBMD estimation at 100 kVp and 120 kVp. The data of 180 patients who underwent abdominal CT imaging and dual-energy X-ray absorptiometry (DXA) within one month were retrospectively collected. vBMD of L1-L4 vertebrae were calculated, and the receiver-operating characteristic curve analysis was performed to establish the diagnostic thresholds for osteoporosis and osteopenia in terms of vBMD. The average difference between the measured vBMD following TCM and the theoretical vBMD of the self-made phantom was 0.2%, and the maximum difference was 0.5%. vBMD of lumbar vertebrae obtained from TCM and aBMD obtained by DXA had a significant positive correlation (r = 0.655 to 0.723). The average diagnostic threshold for osteoporosis was 0.116 g/cm3. The sensitivity, specificity, and accuracy were 95.7%, 75.6.5%, and 80.0%, respectively. The average diagnostic threshold for osteopenia was 0.126 g/cm3. The sensitivity, specificity, and accuracy were 81.3%, 82.5%, and 82.7%, respectively. The aforementioned threshold values were used to perform the diagnostics on a test cohort, and the performance was equivalent to that in the experimental cohort. From the perspective of preventive medicine, opportunistic screening of bone mineral density using abdominal CT images and the TCM approach can facilitate early detection of osteoporosis and osteopenia and, with in-time treatment, slow down their progression.

Effective suppression of myocardial glucose uptake using predesigned low-carbohydrate boxed meals.

BACKGROUND: Dietary preparation protocols are an effective means to suppress physiological myocardial 18F-fluorodeoxyglucose (FDG) uptake. This study aimed to investigate the efficacy of various carbohydrate-restricted diets using predesigned boxed meals. METHODS: The patients were divided into four groups to undergo different preparatory protocols as follows: a minimum 15-hour fast alone, two meals of high-fat, low-carbohydrate diet (HFLCD), two meals of high-animal-protein, low-carbohydrate diet (HAPLCD), and two meals of high-plant-based-protein, low-carbohydrate diet (HPPLCD). Boxed meals were prepared to meet the required carbohydrate restrictions. Myocardial SUVmax and SUVmean were measured and the suppression rate was analyzed. RESULTS: The average myocardial SUVmax of fast alone, HFLCD, HAPLCD, and HPPLCD were 8.26 ± 5.85, 2.21 ± 1.50, 2.34 ± 1.88, and 4.10 ± 3.61, respectively, and the suppression rates were 36.6%, 93.3%, 93.3%, and 70%, respectively. The effectiveness of HFLCD, HAPLCD, and HPPLCD was all statistically superior to that of a 15-hour fast alone. SUVmax of HFLCD and HAPLCD showed no significant differences (p = 1), whereas HFLCD and HPPLCD had significant differences (p = .046). CONCLUSIONS: Using the predesigned boxed meals based on carbohydrate restriction, HFLCD, HAPLCD, and HPPLCD can be administered to patients with different dietary needs while providing a substantial reduction in physiological myocardial FDG uptake.

Model Image-Based Metal Artifact Reduction for Computed Tomography.

Metal implants often produce severe artifacts in the reconstructed computed tomography (CT) images, causing information and image detail loss and making the CT images diagnostically unusable. In order to eliminate the metal artifacts and enhance the diagnostic value of the reconstructed CT images, a post-processing metal artifact reduction algorithm, based on a tissue-class model segmented by thresholding and k-means clustering with spatial information, is proposed. The image inpainting technique is incorporated into the algorithm to improve the segmentation accuracy for CT images severely corrupted by metal artifacts. A study of a water phantom and of two sets of clinical CT images was performed to test the algorithm performance. The proposed method effectively eliminates typical metal artifacts, restores the average CT numbers of different tissues to the proper levels, and preserves the edge and contrast information, thus allowing the accurate reconstruction of the tissue attenuation map. The quality of the artifact-corrected CT images allows them to be subsequently used in other clinical applications, such as three-dimensional rendering, dose estimation for radiotherapy, attenuation correction for PET and SPECT, etc. The algorithm does not rely on the use of the raw sinogram and so is not limited by the proprietary format restrictions.

Using Cine-Averaged CT With the Shallow Breathing Pattern to Reduce Respiration-Induced Artifacts for Thoracic Cavity PET/CT Scans.

OBJECTIVE. PET/CT provides a fusion of both anatomic and functional information. However, because of the temporal difference of both modalities and respiratory motion of lungs, misregistration of lesions is frequently observed on thoracic PET/CT scans. The effect of cine-averaged CT (CACT) acquisition incorporated with the shallow breathing pattern of patients on the improvement of registration and quantification of lesions was investigated. MATERIALS AND METHODS. Thirty patients with cancer who underwent routine PET/CT followed by CACT of the thoracic region were enrolled. The misalignment between PET/helical CT (HCT) and PET/CACT was calculated. In addition, the PET data were attenuation-corrected by HCT and CACT images, and the maximum standardized uptake value (SUVmax) was evaluated. RESULTS. All lesions in the PET/HCT images showed misalignment larger than 5 mm, whereas only 33% of lesions in the PET/CACT images showed misalignment larger than 5 mm. The mean values of the maximum misalignment of the lesions in PET/HCT and PET/CACT images were 14.10 ± 6.26 mm and 5.92 ± 4.31 mm, respectively. Seven percent of the lesions had an increase in SUVmax of more than 20%, and 47% showed a slight increase in SUVmax of less than 5% after applying CACT. The mean percentage difference between the SUVmax of CACT and that of HCT was 12%. CONCLUSION. Using the CACT technique and the shallow breathing pattern effectively reduces misregistration of lesions and recovers the underestimated SUVmax. The CACT method can be applied in clinical practice of thoracic PET/CT for better cancer management.

Investigation of nematic to smectic phase transition and dynamical properties of strongly confined semiflexible polymers using Langevin dynamics.

We investigated the nematic to smectic phase transition for strongly confined semiflexible polymer solutions in slit-like confinements using GPU-accelerated Langevin dynamics. We characterized the phase transitions from the nematic to smectic phases for semi-flexible polymer solutions as the polymer density increased. The dependence for the lyotropic nematic to smectic transition can be collapsed by scaling exponents between 0.2 and 0.3. The smectic C phase is found for all the cases with the polymer orientation director tilted with respect to smectic layer lateral alignment. As the chain rigidity increases, the transition density decreases for systems in which the polymer persistence length (P) to slit height (H) ratios are 1.25, 2.5, 3.75, 5 and 25. We also characterized the polymer dynamics for the isotropic-nematic-smectic transitions. The overall polymer diffusivity decreased steadily as the polymer density increased. We observed anomalous polymer diffusion along the nematic director near the isotropic-nematic transition, similar to previously reported behavior for nematic-forming ellipsoids. Polymer diffusivity decreased sharply by two orders of magnitude upon the nematic-smectic transition.

Quantification of Volumetric Bone Mineral Density of Proximal Femurs Using a Two-Compartment Model and Computed Tomography Images.

OBJECTIVES: Dual-energy X-ray absorptiometry (DXA) is frequently used to measure the areal bone mineral density (aBMD) in clinical practice. However, DXA measurements are affected by the bone thickness and the body size and are unable to indicate nonosseous areas within the trabecular bone. This study aims to quantify the volumetric bone mineral density (vBMD) using computed tomography (CT) images and the two-compartment model (TCM) methods. METHODS: The TCM method was proposed and validated by dipotassium phosphate (K2HPO4) phantoms and a standard forearm phantom. 28 cases with DXA scans and pelvic CT scans acquired within six months were retrospectively collected. The vBMD calculated by TCM was compared with the aBMD obtained from DXA. RESULTS: For the K2HPO4 phantoms with vBMD ranging from 0.135 to 0.467 g/cm3, the average difference between the real and calculated vBMD was 0.009 g/cm3 and the maximum difference was 0.019 g/cm3. For the standard forearm phantom with vBMD of 0.194, 0.103, and 0.054 g/cm3, the average differences between the real and calculated vBMD were 0.017, 0.014, and 0.011 g/cm3. In the clinical CT image validation, a good linear relationship between vBMD and aBMD was observed with the Pearson correlation coefficient of 0.920 (p < 0.01). CONCLUSIONS: The proposed TCM method in combination with the homemade cortical bone equivalent phantom provides accurate quantification and spatial distribution of bone mineral content.

Four patients with gastrointestinal bleeding identified by a modified in vivo technique with labeled red blood cells sedimentation.

OBJECTIVE: Gastrointestinal bleeding scintigraphy (GIBS) offers the advantage of continuous monitoring of patients to localize the site of gastrointestinal bleeding. In this study, a modified in vivo labeling method with sedimentation of the labeled red blood cells (RBC) was applied to remove free technetium-99m (99mTc) and increase labeling efficiency. PATIENTS AND METHODS: Four patients were studied. A modified in vivo RBC labeling method was used. After 10 minutes of RBC sedimentation, patients' blood plasma in the upper part of the syringe was removed, and the erythrocytes labeled with 99mTc were re-administered to the patient. Serial dynamic scintiphotos were taken during the first 60 minutes. Delayed static images were acquired up to 22 hours after injection. RESULTS: The labeling efficiency of 99mTc-RBC increased up to 93%. GIBS can be performed after 20 hours post-injection and provide accurate diagnosis of gastrointestinal bleeding. No false positive findings due to free 99mTc accumulation were observed for the four patients. CONCLUSION: The modified in vivo method with sedimentation is a simple and effective way to increase the labeling efficiency and thus the diagnosis for the detection of gastrointestinal bleeding.

Entropic attraction: Polymer compaction and expansion induced by nano-particles in confinement.

We investigated nanoparticle (NP)-induced coil-to-globule transition of a semi-flexible polymer in a confined suspension of ideal NP using Langevin dynamics. DNA molecules are often found to be highly compact, bound with oppositely charged proteins in a crowded environment within cells and viruses. Recent studies found that high concentration of electrostatically neutral NP also condenses DNA due to entropically induced depletion attraction between DNA segments. Langevin dynamics simulations with a semi-flexible chain under strong confinement were performed to investigate the competition between NP-induced monomer-monomer and monomer-wall attraction under different confinement heights and NP volume fractions. We found that whether NP induce polymer segments to adsorb to the walls and swell or to attract one another and compact strongly depends on the relative strength of the monomer-wall and the NP-wall interactions.