A Bayesian Nonparametric model for textural pattern heterogeneity

Cancer radiomics is an emerging discipline promising to elucidate lesion phenotypes and tumor heterogeneity through patterns of enhancement, texture, morphology, and shape. The prevailing technique for image texture analysis relies on the construction and synthesis of Gray-Level Co-occurrence Matrices (GLCM). Practice currently reduces the structured count data of a GLCM to reductive and redundant summary statistics for which analysis requires variable selection and multiple comparisons for each application, thus limiting reproducibility. In this article, we develop a Bayesian multivariate probabilistic framework for the analysis and unsupervised clustering of a sample of GLCM objects. By appropriately accounting for skewness and zero-inflation of the observed counts and simultaneously adjusting for existing spatial autocorrelation at nearby cells, the methodology facilitates estimation of texture pattern distributions within the GLCM lattice itself. The techniques are applied to cluster images of adrenal lesions obtained from CT scans with and without administration of contrast. We further assess whether the resultant subtypes are clinically oriented by investigating their correspondence with pathological diagnoses. Additionally, we compare performance to a class of machine-learning approaches currently used in cancer radiomics with simulation studies.Comment: 45 pages, 7 figures, 1 Tabl

Radiomics in Cross-Sectional Adrenal Imaging: A Systematic Review and Quality Assessment Study

In this study, we aimed to systematically review the current literature on radiomics applied to cross-sectional adrenal imaging and assess its methodological quality. Scopus, PubMed and Web of Science were searched to identify original research articles investigating radiomics applications on cross-sectional adrenal imaging (search end date February 2021). For qualitative synthesis, details regarding study design, aim, sample size and imaging modality were recorded as well as those regarding the radiomics pipeline (e.g., segmentation and feature extraction strategy). The methodological quality of each study was evaluated using the radiomics quality score (RQS). After duplicate removal and selection criteria application, 25 full-text articles were included and evaluated. All were retrospective studies, mostly based on CT images (17/25, 68%), with manual (19/25, 76%) and two-dimensional segmentation (13/25, 52%) being preferred. Machine learning was paired to radiomics in about half of the studies (12/25, 48%). The median total and percentage RQS scores were 2 (interquartile range, IQR = −5–8) and 6% (IQR = 0–22%), respectively. The highest and lowest scores registered were 12/36 (33%) and −5/36 (0%). The most critical issues were the absence of proper feature selection, the lack of appropriate model validation and poor data openness. The methodological quality of radiomics studies on adrenal cross-sectional imaging is heterogeneous and lower than desirable. Efforts toward building higher quality evidence are essential to facilitate the future translation into clinical practice

Quantitative PET and SPECT

Since the introduction of personalized medicine, the primary focus of imaging has moved from detection and diagnosis to tissue characterization, the determination of prognosis, prediction of treatment efficacy, and measurement of treatment response. Precision (personalized) imaging heavily relies on the use of hybrid technologies and quantitative imaging biomarkers. The growing number of promising theragnostics require accurate quantification for pre- and post-treatment dosimetry. Furthermore, quantification is required in the pharmacokinetic analysis of new tracers and drugs and in the assessment of drug resistance. Positron Emission Tomography (PET) is, by nature, a quantitative imaging tool, relating the time–activity concentration in tissues and the basic functional parameters governing the biological processes being studied. Recent innovations in single photon emission computed tomography (SPECT) reconstruction techniques have allowed for SPECT to move from relative/semi-quantitative measures to absolute quantification. The strength of PET and SPECT is that they permit whole-body molecular imaging in a noninvasive way, evaluating multiple disease sites. Furthermore, serial scanning can be performed, allowing for the measurement of functional changes over time during therapeutic interventions. This Special Issue highlights the hot topics on quantitative PET and SPECT

Advanced Imaging Analysis for Predicting Tumor Response and Improving Contour Delineation Uncertainty

ADVANCED IMAGING ANALYSIS FOR PREDICTING TUMOR RESPONSE AND IMPROVING CONTOUR DELINEATION UNCERTAINTY By Rebecca Nichole Mahon, MS A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2018 Major Director: Dr. Elisabeth Weiss, Professor, Department of Radiation Oncology Radiomics, an advanced form of imaging analysis, is a growing field of interest in medicine. Radiomics seeks to extract quantitative information from images through use of computer vision techniques to assist in improving treatment. Early prediction of treatment response is one way of improving overall patient care. This work seeks to explore the feasibility of building predictive models from radiomic texture features extracted from magnetic resonance (MR) and computed tomography (CT) images of lung cancer patients. First, repeatable primary tumor texture features from each imaging modality were identified to ensure a sufficient number of repeatable features existed for model development. Then a workflow was developed to build models to predict overall survival and local control using single modality and multi-modality radiomics features. The workflow was also applied to normal tissue contours as a control study. Multiple significant models were identified for the single modality MR- and CT-based models, while the multi-modality models were promising indicating exploration with a larger cohort is warranted. Another way advances in imaging analysis can be leveraged is in improving accuracy of contours. Unfortunately, the tumor can be close in appearance to normal tissue on medical images creating high uncertainty in the tumor boundary. As the entire defined target is treated, providing physicians with additional information when delineating the target volume can improve the accuracy of the contour and potentially reduce the amount of normal tissue incorporated into the contour. Convolution neural networks were developed and trained to identify the tumor interface with normal tissue and for one network to identify the tumor location. A mock tool was presented using the output of the network to provide the physician with the uncertainty in prediction of the interface type and the probability of the contour delineation uncertainty exceeding 5mm for the top three predictions

Automated Characterisation and Classification of Liver Lesions From CT Scans

Cancer is a general term for a wide range of diseases that can affect any part of the body due to the rapid creation of abnormal cells that grow outside their normal boundaries. Liver cancer is one of the common diseases that cause the death of more than 600,000 each year. Early detection is important to diagnose and reduce the incidence of death. Examination of liver lesions is performed with various medical imaging modalities such as Ultrasound (US), Computer tomography (CT), and Magnetic resonance imaging (MRI). The improvements in medical imaging and image processing techniques have significantly enhanced the interpretation of medical images. Computer-Aided Diagnosis (CAD) systems based on these techniques play a vital role in the early detection of liver disease and hence reduce liver cancer death rate. Moreover, CAD systems can help physician, as a second opinion, in characterising lesions and making the diagnostic decision. Thus, CAD systems have become an important research area. Particularly, these systems can provide diagnostic assistance to doctors to improve overall diagnostic accuracy. The traditional methods to characterise liver lesions and differentiate normal liver tissues from abnormal ones are largely dependent on the radiologists experience. Thus, CAD systems based on the image processing and artificial intelligence techniques gained a lot of attention, since they could provide constructive diagnosis suggestions to clinicians for decision making. The liver lesions are characterised through two ways: (1) Using a content-based image retrieval (CBIR) approach to assist the radiologist in liver lesions characterisation. (2) Calculating the high-level features that describe/ characterise the liver lesion in a way that is interpreted by humans, particularly Radiologists/Clinicians, based on the hand-crafted/engineered computational features (low-level features) and learning process. However, the research gap is related to the high-level understanding and interpretation of the medical image contents from the low-level pixel analysis, based on mathematical processing and artificial intelligence methods. In our work, the research gap is bridged if a relation of image contents to medical meaning in analogy to radiologist understanding is established. This thesis explores an automated system for the classification and characterisation of liver lesions in CT scans. Firstly, the liver is segmented automatically by using anatomic medical knowledge, histogram-based adaptive threshold and morphological operations. The lesions and vessels are then extracted from the segmented liver by applying AFCM and Gaussian mixture model through a region growing process respectively. Secondly, the proposed framework categorises the high-level features into two groups; the first group is the high-level features that are extracted from the image contents such as (Lesion location, Lesion focality, Calcified, Scar, ...); the second group is the high-level features that are inferred from the low-level features through machine learning process to characterise the lesion such as (Lesion density, Lesion rim, Lesion composition, Lesion shape,...). The novel Multiple ROIs selection approach is proposed, in which regions are derived from generating abnormality level map based on intensity difference and the proximity distance for each voxel with respect to the normal liver tissue. Then, the association between low-level, high-level features and the appropriate ROI are derived by assigning the ability of each ROI to represents a set of lesion characteristics. Finally, a novel feature vector is built, based on high-level features, and fed into SVM for lesion classification. In contrast with most existing research, which uses low-level features only, the use of high-level features and characterisation helps in interpreting and explaining the diagnostic decision. The methods are evaluated on a dataset containing 174 CT scans. The experimental results demonstrated that the efficacy of the proposed framework in the successful characterisation and classification of the liver lesions in CT scans. The achieved average accuracy was 95:56% for liver lesion characterisation. While the lesion’s classification accuracy was 97:1% for the entire dataset. The proposed framework is developed to provide a more robust and efficient lesion characterisation framework through comprehensions of the low-level features to generate semantic features. The use of high-level features (characterisation) helps in better interpretation of CT liver images. In addition, the difference-of-features using multiple ROIs were developed for robust capturing of lesion characteristics in a reliable way. This is in contrast to the current research trend of extracting the features from the lesion only and not paying much attention to the relation between lesion and surrounding area. The design of the liver lesion characterisation framework is based on the prior knowledge of the medical background to get a better and clear understanding of the liver lesion characteristics in medical CT images

Epilepsy

Epilepsy is the most common neurological disorder globally, affecting approximately 50 million people of all ages. It is one of the oldest diseases described in literature from remote ancient civilizations 2000-3000 years ago. Despite its long history and wide spread, epilepsy is still surrounded by myth and prejudice, which can only be overcome with great difficulty. The term epilepsy is derived from the Greek verb epilambanein, which by itself means to be seized and to be overwhelmed by surprise or attack. Therefore, epilepsy is a condition of getting over, seized, or attacked. The twelve very interesting chapters of this book cover various aspects of epileptology from the history and milestones of epilepsy as a disease entity, to the most recent advances in understanding and diagnosing epilepsy

Machine Learning Assisted Digital Pathology

Histopatologiset kudosnäytteet sisältävät valtavan määrän tietoa biologisista mekanismeista, jotka vaikuttavat monien tautien ilmenemiseen ja etenemiseen. Tästä syystä histopatologisten näytteiden arviointi on ollut perustana monien tautien diagnostiikassa vuosikymmenien ajan. Perinteinen histopatologinen arviointi on kuitenkin työläs tehtävä ja lisäksi erittäin altis inhimillisille virheille ja voi siten johtaa virheelliseen tai viivästyneeseen diagnoosiin. Viime vuosien teknologinen kehitys on tuonut patologien käyttöön lasiskannerit ja tiedonhallintajarjestelmät ja sitä myötä mahdollistaneet näytelasien digitoinnin ja käynnistäneet koko patologian työnkulun digitalisaation. Histopatologisten näytteiden saatavuus digitaalisina kuvina on puolestaan mahdollistanut älykkäiden algoritmien ja automatisoitujen laskennallisten kuva-analyysityökalujen kehittämisen diagnostiikan tueksi. Koneoppiminen on tekoälyn osa-alue, joka voidaan määritellä datasta oppimiseksi. Kuva-analyysin sovelluksissa, kuvan pikseliarvot muutetaan kvantitatiiviseksi piirre-esitykseksi jonka pohjalta kuva voidaan muuntaa merkitykselliseksi tiedoksi hyvödyntämällä koneoppimista. Vuosien saatossa koneoppimiseen perustuvan kuva-analyysin menetelmät ovat kehittyneet manuaalisesta piirteidenirroituksesta kohti viimevuosien vallitsevia syväoppimiseen pohjautuvia konvoluutioneuroverkkoja. Koneoppimisen hyödyt histopatologisessa arvioinnissa ovat huomattavat, sillä koneoppiminen mahdollistaa kuvien tulkinnan patologiin verrattavalla tarkkuudella ja siten pystyy merkittävästi parantamaan kliinisen patologian diagnostiikan tarkkuutta, toistettavuutta ja tehokkuutta. Tämä väitöstyö esittelee koneoppimiseen pohjautuvia menetelmiä jotka on kehitetty avustamaan kudosnäytteen histopatologista arviointia, vaihetta joka on merkityksellinen niin kliinisessä diagnostiikassa kuin prekliinisissä tutkimuksissa. Työssä esitellään piirteenirroituksen ja koneoppimisen tehokkuus histopatologiseen arviointiin liittyvissä kuva-analyysitehtävissä kuten kudoksen karakterisoinnissa, sekä rintasyövän etäpesäkkeiden, epiteelikudoksen ja tumien tunnistuksessa. Menetelmien lisäksi tässä väitöstyössä on käsitelty keskeisiä haasteita jotka on huomioitava integroitaessa koneoppimismenetelmiä kliiniseen käyttöön. Ennen kaikkea nämä tutkimukset ovat kuitenkin osoittaneet koneoppimisen mahdollisuudet tulevaisuudessa parantaa patologian kliinisten rutiinitehtävien tehokkuutta ja toistettavuutta sekä diagnostiikan laatua.Histopathological tissue samples contain a vast amount of information on underlying biological mechanisms that contribute to disease manifestation and progression. Therefore, diagnosis from histopathological tissue samples has been the gold standard for decades. However, traditional histopathological assessment is a laborious task and prone to human errors, thereby leading to misdiagnosis or delayed diagnosis. The development of whole slide scanners for digitization of tissue glass slides has initiated the transition to a fully digital pathology workflow that allows scanning, interpretation, and management of digital tissue slides. These advances have been the cornerstone for developing intelligent algorithms and automated computational approaches for histopathological assessment and clinical diagnostics. Machine learning is a subcategory of artificial intelligence and can be defined as a process of learning from data. In image analysis tasks, the raw pixel values are transformed into quantitative feature representations. Based on the image data representation, a machine learning model learns a set of rules that can be used to extract meaningful information and knowledge. Over the years, the field of machine learning based image analysis has developed from manually handcrafting complex features to the recent revolution of deep learning and convolutional neural networks. Histopathological assessment can benefit greatly from the ability of machine learning models to discover patterns and connections from the data. Therefore, machine learning holds great promise to improve the accuracy, reproducibility, and efficiency of clinical diagnostics in the field of digital pathology. This thesis is focused on developing machine learning based methods for assisting in the process of histopathological assessment, which is a significant step in clinical diagnostics as well as in preclinical studies. The studies presented in this thesis show the effectiveness of feature engineering and machine learning in histopathological assessment related tasks, such as; tissue characterisation, metastasis detection, epithelial tissue detection, and nuclei detection. Moreover, the studies presented in this thesis address the key challenges related to variation presented in histopathological data as well as the generalisation problem that need to be considered in order to integrate machine learning approaches into clinical practice. Overall, these studies have demonstrated the potential of machine learning for bringing standardization and reproducibility to the process of histopathological assessment

[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)