Improved Modeling and Image Generation for Fluorescence Molecular Tomography (FMT) and Positron Emission Tomography (PET)

In this thesis, we aim to improve quantitative medical imaging with advanced image generation algorithms. We focus on two specific imaging modalities: fluorescence molecular tomography (FMT) and positron emission tomography (PET). For FMT, we present a novel photon propagation model for its forward model, and in addition, we propose and investigate a reconstruction algorithm for its inverse problem. In the first part, we develop a novel Neumann-series-based radiative transfer equation (RTE) that incorporates reflection boundary conditions in the model. In addition, we propose a novel reconstruction technique for diffuse optical imaging that incorporates this Neumann-series-based RTE as forward model. The proposed model is assessed using a simulated 3D diffuse optical imaging setup, and the results demonstrate the importance of considering photon reflection at boundaries when performing photon propagation modeling. In the second part, we propose a statistical reconstruction algorithm for FMT. The algorithm is based on sparsity-initialized maximum-likelihood expectation maximization (MLEM), taking into account the Poisson nature of data in FMT and the sparse nature of images. The proposed method is compared with a pure sparse reconstruction method as well as a uniform-initialized MLEM reconstruction method. Results indicate the proposed method is more robust to noise and shows improved qualitative and quantitative performance. For PET, we present an MRI-guided partial volume correction algorithm for brain imaging, aiming to recover qualitative and quantitative loss due to the limited resolution of PET system, while keeping image noise at a low level. The proposed method is based on an iterative deconvolution model with regularization using parallel level sets. A non-smooth optimization algorithm is developed so that the proposed method can be feasibly applied for 3D images and avoid additional blurring caused by conventional smooth optimization process. We evaluate the proposed method using both simulation data and in vivo human data collected from the Baltimore Longitudinal Study of Aging (BLSA). Our proposed method is shown to generate images with reduced noise and improved structure details, as well as increased number of statistically significant voxels in study of aging. Results demonstrate our method has promise to provide superior performance in clinical imaging scenarios

Compressed Sensing Beyond the IID and Static Domains: Theory, Algorithms and Applications

Sparsity is a ubiquitous feature of many real world signals such as natural images and neural spiking activities. Conventional compressed sensing utilizes sparsity to recover low dimensional signal structures in high ambient dimensions using few measurements, where i.i.d measurements are at disposal. However real world scenarios typically exhibit non i.i.d and dynamic structures and are confined by physical constraints, preventing applicability of the theoretical guarantees of compressed sensing and limiting its applications. In this thesis we develop new theory, algorithms and applications for non i.i.d and dynamic compressed sensing by considering such constraints. In the first part of this thesis we derive new optimal sampling-complexity tradeoffs for two commonly used processes used to model dependent temporal structures: the autoregressive processes and self-exciting generalized linear models. Our theoretical results successfully recovered the temporal dependencies in neural activities, financial data and traffic data. Next, we develop a new framework for studying temporal dynamics by introducing compressible state-space models, which simultaneously utilize spatial and temporal sparsity. We develop a fast algorithm for optimal inference on such models and prove its optimal recovery guarantees. Our algorithm shows significant improvement in detecting sparse events in biological applications such as spindle detection and calcium deconvolution. Finally, we develop a sparse Poisson image reconstruction technique and the first compressive two-photon microscope which uses lines of excitation across the sample at multiple angles. We recovered diffraction-limited images from relatively few incoherently multiplexed measurements, at a rate of 1.5 billion voxels per second

Comprehensive mapping of tissue cell architecture via integrated single cell and spatial transcriptomics

elocation-id: 2020.11.15.378125elocation-id: 2020.11.15.378125The spatial organization of cell types in tissues fundamentally shapes cellular interactions and function, but the high-throughput spatial mapping of complex tissues remains a challenge. We present сell2location, a principled and versatile Bayesian model that integrates single-cell and spatial transcriptomics to map cell types in situ in a comprehensive manner. We show that сell2location outperforms existing tools in accuracy and comprehensiveness and we demonstrate its utility by mapping two complex tissues. In the mouse brain, we use a new paired single nucleus and spatial RNA-sequencing dataset to map dozens of cell types and identify tissue regions in an automated manner. We discover novel regional astrocyte subtypes including fine subpopulations in the thalamus and hypothalamus. In the human lymph node, we resolve spatially interlaced immune cell states and identify co-located groups of cells underlying tissue organisation. We spatially map a rare pre-germinal centre B-cell population and predict putative cellular interactions relevant to the interferon response. Collectively our results demonstrate how сell2location can serve as a versatile first-line analysis tool to map tissue architectures in a high-throughput manner.Competing Interest StatementThe authors have declared no competing interest

Computational phase imaging for biomedical applications

When a sample is illuminated by an imaging field, its fingerprints are left on the amplitude and the phase of the emerging wave. Capturing the information of the wavefront grants us a deeper understanding of the optical properties of the sample, and of the light-matter interaction. While the amplitude information has been intensively studied, the use of the phase information has been less common. Because all detectors are sensitive to intensity, not phase, wavefront measurements are significantly more challenging. Deploying optical interferometry to measure phase through phase-intensity conversion, quantitative phase imaging (QPI) has recently gained tremendous success in material and life sciences. The first topic of this dissertation describes our effort to develop a new QPI setup, named transmission Spatial Light Interference Microscopy (tSLIM), that uses the twisted nematic liquid-crystal (TNLC) modulators. Compared to the established SLIM technique, tSLIM is much less expensive to build than its predecessor (SLIM) while maintaining significant performance. The tSLIM system uses parallel aligned liquid-crystal (PANLC) modulators, has a slightly smaller signal-to-noise Ratio (SNR), and a more complicated model for the image formation. However, such complexity is well addressed by computing. Most importantly, tSLIM uses TNLC modulators that are popular in display LCDs. Therefore, the total cost of the system is significantly reduced. Alongside developing new imaging modalities, we also improved current QPI imaging systems. In practice, an incident field to the sample is rarely perfectly spatially coherent, i.e., plane wave. It is generally partially coherent; i.e., it comprises of many incoherent plane waves coming from multiple directions. This illumination yields artifacts in the phase measurement results, e.g., halo and phase-underestimation. One solution is using a very bright source, e.g., a laser, which can be spatially filtered very well. However, the laser comes at the expense of speckles, which degrades image quality. Therefore, solutions purely based on physical modeling and computations to remove these artifacts, using white-light illumination, are highly desirable. Here, using physical optics, we develop a theoretical model that accurately explains the effects of partial coherence on image information and phase information. The model is further combined with numerical processing to suppress the artifacts, and recover the correct phase information. The third topic is devoted to applying QPI to clinical applications. Traditionally, stained tissues are used in prostate cancer diagnosis instead. The reason is that tissue samples used in diagnosis are nearly transparent under bright field inspection if unstained. Contrast-enhanced microscopy techniques, e.g., phase contrast microscopy (PC) and differential interference contrast microscopy (DIC), can render visibility of the untagged samples with high throughput. However, since these methods are intensity-based, the contrast of acquired images varies significantly from one imaging facility to another, preventing them from being used in diagnosis. Inheriting the merits of PC, SLIM produces phase maps, which measure the refractive index of label-free samples. However, the maps measured by SLIM are not affected by variation in imaging conditions, e.g., illumination, magnification, etc., allowing consistent imaging results when using SLIM across different clinical institutions. Here, we combine SLIM images with machine learning for automatic diagnosis results for prostate cancer. We focus on two diagnosis problems of automatic Gleason grading and cancer vs. non-cancer diagnosis. Finally, we introduce a new imaging modality, named Gradient Light Interference Microscopy (GLIM), which is able to image through optically thick samples using low spatial coherence illumination. The key benefit of GLIM comes from a large numerical aperture of the condenser, which is 0.55 NA, about five times higher than that in SLIM. GLIM has an excellent depth sectioning when recording three-dimensional information of the susceptibility of the sample. We also introduce a model for the image formation of GLIM with an implication that a simple filtering step in the transverse dimension can dramatically improve the sectioning in the axial dimension. With GLIM, one can measure accurately the surface area, volume, and dry mass of a variety of biological samples, ranging from cells that are about tens of microns thick to bovine embryos that are hundreds of microns thick

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)

Single Cell Analysis

Cells are the most fundamental building block of all living organisms. The investigation of any type of disease mechanism and its progression still remains challenging due to cellular heterogeneity characteristics and physiological state of cells in a given population. The bulk measurement of millions of cells together can provide some general information on cells, but it cannot evolve the cellular heterogeneity and molecular dynamics in a certain cell population. Compared to this bulk or the average measurement of a large number of cells together, single-cell analysis can provide detailed information on each cell, which could assist in developing an understanding of the specific biological context of cells, such as tumor progression or issues around stem cells. Single-cell omics can provide valuable information about functional mutation and a copy number of variations of cells. Information from single-cell investigations can help to produce a better understanding of intracellular interactions and environmental responses of cellular organelles, which can be beneficial for therapeutics development and diagnostics purposes. This Special Issue is inviting articles related to single-cell analysis and its advantages, limitations, and future prospects regarding health benefits

The anthropometric, environmental and genetic determinants of right ventricular structure and function

BACKGROUND Measures of right ventricular (RV) structure and function have significant prognostic value. The right ventricle is currently assessed by global measures, or point surrogates, which are insensitive to regional and directional changes. We aim to create a high-resolution three-dimensional RV model to improve understanding of its structural and functional determinants. These may be particularly of interest in pulmonary hypertension (PH), a condition in which RV function and outcome are strongly linked. PURPOSE To investigate the feasibility and additional benefit of applying three-dimensional phenotyping and contemporary statistical and genetic approaches to large patient populations. METHODS Healthy subjects and incident PH patients were prospectively recruited. Using a semi-automated atlas-based segmentation algorithm, 3D models characterising RV wall position and displacement were developed, validated and compared with anthropometric, physiological and genetic influences. Statistical techniques were adapted from other high-dimensional approaches to deal with the problems of multiple testing, contiguity, sparsity and computational burden. RESULTS 1527 healthy subjects successfully completed high-resolution 3D CMR and automated segmentation. Of these, 927 subjects underwent next-generation sequencing of the sarcomeric gene titin and 947 subjects completed genotyping of common variants for genome-wide association study. 405 incident PH patients were recruited, of whom 256 completed phenotyping. 3D modelling demonstrated significant reductions in sample size compared to two-dimensional approaches. 3D analysis demonstrated that RV basal-freewall function reflects global functional changes most accurately and that a similar region in PH patients provides stronger survival prediction than all anthropometric, haemodynamic and functional markers. Vascular stiffness, titin truncating variants and common variants may also contribute to changes in RV structure and function. CONCLUSIONS High-resolution phenotyping coupled with computational analysis methods can improve insights into the determinants of RV structure and function in both healthy subjects and PH patients. Large, population-based approaches offer physiological insights relevant to clinical care in selected patient groups.Open Acces

Discriminative Representations for Heterogeneous Images and Multimodal Data

Histology images of tumor tissue are an important diagnostic and prognostic tool for pathologists. Recently developed molecular methods group tumors into subtypes to further guide treatment decisions, but they are not routinely performed on all patients. A lower cost and repeatable method to predict tumor subtypes from histology could bring benefits to more cancer patients. Further, combining imaging and genomic data types provides a more complete view of the tumor and may improve prognostication and treatment decisions. While molecular and genomic methods capture the state of a small sample of tumor, histological image analysis provides a spatial view and can identify multiple subtypes in a single tumor. This intra-tumor heterogeneity has yet to be fully understood and its quantification may lead to future insights into tumor progression. In this work, I develop methods to learn appropriate features directly from images using dictionary learning or deep learning. I use multiple instance learning to account for intra-tumor variations in subtype during training, improving subtype predictions and providing insights into tumor heterogeneity. I also integrate image and genomic features to learn a projection to a shared space that is also discriminative. This method can be used for cross-modal classification or to improve predictions from images by also learning from genomic data during training, even if only image data is available at test time.Doctor of Philosoph