A Review on Data Fusion of Multidimensional Medical and Biomedical Data

Data fusion aims to provide a more accurate description of a sample than any one source of data alone. At the same time, data fusion minimizes the uncertainty of the results by combining data from multiple sources. Both aim to improve the characterization of samples and might improve clinical diagnosis and prognosis. In this paper, we present an overview of the advances achieved over the last decades in data fusion approaches in the context of the medical and biomedical fields. We collected approaches for interpreting multiple sources of data in different combinations: image to image, image to biomarker, spectra to image, spectra to spectra, spectra to biomarker, and others. We found that the most prevalent combination is the image-to-image fusion and that most data fusion approaches were applied together with deep learning or machine learning methods

Mass spectral imaging of clinical samples using deep learning

A better interpretation of tumour heterogeneity and variability is vital for the improvement of novel diagnostic techniques and personalized cancer treatments. Tumour tissue heterogeneity is characterized by biochemical heterogeneity, which can be investigated by unsupervised metabolomics. Mass Spectrometry Imaging (MSI) combined with Machine Learning techniques have generated increasing interest as analytical and diagnostic tools for the analysis of spatial molecular patterns in tissue samples. Considering the high complexity of data produced by the application of MSI, which can consist of many thousands of spectral peaks, statistical analysis and in particular machine learning and deep learning have been investigated as novel approaches to deduce the relationships between the measured molecular patterns and the local structural and biological properties of the tissues. Machine learning have historically been divided into two main categories: Supervised and Unsupervised learning. In MSI, supervised learning methods may be used to segment tissues into histologically relevant areas e.g. the classification of tissue regions in H&E (Haemotoxylin and Eosin) stained samples. Initial classification by an expert histopathologist, through visual inspection enables the development of univariate or multivariate models, based on tissue regions that have significantly up/down-regulated ions. However, complex data may result in underdetermined models, and alternative methods that can cope with high dimensionality and noisy data are required. Here, we describe, apply, and test a novel diagnostic procedure built using a combination of MSI and deep learning with the objective of delineating and identifying biochemical differences between cancerous and non-cancerous tissue in metastatic liver cancer and epithelial ovarian cancer. The workflow investigates the robustness of single (1D) to multidimensional (3D) tumour analyses and also highlights possible biomarkers which are not accessible from classical visual analysis of the H&E images. The identification of key molecular markers may provide a deeper understanding of tumour heterogeneity and potential targets for intervention.Open Acces

Study on comparison of biochemistry between Trogoderma granarium Everts and Trogoderma variabile Ballion

Stored grains are paramount commodities to be preserved and stocked for future supply to the market according to the requirement. However, one of the major problems during storage is insect pests, of which insects from Trogoderma sp. especially khapra beetle (Trogoderma granarium) is considered the world most dangerous stored grain insect pests. Therefore, it has been listed as quarantine insect pests in many counties. For timely management of quarantine pest, effective and rapid diagnostic methods are required. Until now, diagnostic technology is mainly based on morphology of insects which require trained taxonomists. Recently, diagnostics based on metabolites and hyperspectral imaging coupled with machine learning is gaining importance. However, very little is known about the metabolites in Trogoderma sp. and how the host grain, gender, and geographical distribution affect the metabolomic profiling in these species is still unknown. In this thesis, volatile organic compounds (VOCs) emitted by Trogoderma variabile at different life stages were analysed as biomarkers which can help us to understand the biochemistry and metabolomic. Some compounds were identified from T. variabile different stages, which could be used as diagnostic tool for this insect. Gas chromatography coupled to mass spectrometry (GC–MS) was used as a technique to study the metabolite profile of T. variabile in different host grains. However, there are several factors that affect the volatile organic compounds including extraction time and number of insects. The results indicated that the optimal number of insects required for volatile organic compounds (VOC) extraction at each life stage was 25 and 20 for larvae and adults respectively. Sixteen hours were selected as the optimal extraction time for larvae and adults. Some of the VOCs compounds identified from this insect can be used as biomarkers such as pentanoic acid; diethoxymethyl acetate; 1-decyne; naphthalene, 2-methyl-; n-decanoic acid; dodecane, 1-iodo- and m-camphorene from larvae. While butanoic acid, 2-methyl-; pentanoic acid; heptane, 1,1'-oxybis- 2(3H)-Furanone, 5-ethyldihydro-; pentadecane, 2,6,10-trimethyl-; and 1,14-tetradecanediol VOCs, were found in male, whereas pentadecane; nonanic acid; pentadecane, 2,6,10-trimethyl-; undecanal and hexadecanal were identified from female. Additionaly, direct immersion-solid phase microextraction (DI-SPME) was employed, followed by gas chromatography mass spectrometry analysis (GC-MS) for the collection, separation, and identification of the chemical compounds from T. variabile adults fed on four different host grains. Results showed that insect host grains have a significant difference on the chemical compounds that were identified from female and male. There were 23 compounds identified from adults reared on canola and wheat. However, there were 26 and 28 compounds detected from adults reared on oats and barley respectively. Results showed that 11-methylpentacosane; 13-methylheptacosane; heptacosane; docosane, 1-iodo- and nonacosane were the most significant compounds that identified form T. variabile male reared on different host grains. However, the main compounds identified from female cultured on different host grains include docosane, 1-iodo-; 1-butanamine, N-butyl-; oleic acid; heptacosane; 13-methylheptacosane; hexacosane; nonacosane; 2-methyloctacosane; n-hexadecanoic acid and docosane. A novel diagnostic tool to identify between T. granarium and T. variabile were developed using visible near infrared hyperspectral imaging and deep learning models including Convolutional Neural Networks (CNN) and Capsule Network. Ventral orientation showed a better accuracy over dorsal orientation of the insects for both larvae and adult stages. This technology offers a new approach and possibility of an effective identification of T. granarium and T. variabile. from its body fragments and larvae skins. The results showed high accuracy to identify between T. granarium and T. variabile. The accuracy was 93.4 and 96.2% for adults and larvae respectively, and the accuracies of 91.6, 91.7 and 90.3% were achieved for larvae skin, adult fragments, larvae fragment respectively

Advances in neuroproteomics for neurotrauma: unraveling insights for personalized medicine and future prospects

Neuroproteomics, an emerging field at the intersection of neuroscience and proteomics, has garnered significant attention in the context of neurotrauma research. Neuroproteomics involves the quantitative and qualitative analysis of nervous system components, essential for understanding the dynamic events involved in the vast areas of neuroscience, including, but not limited to, neuropsychiatric disorders, neurodegenerative disorders, mental illness, traumatic brain injury, chronic traumatic encephalopathy, and other neurodegenerative diseases. With advancements in mass spectrometry coupled with bioinformatics and systems biology, neuroproteomics has led to the development of innovative techniques such as microproteomics, single-cell proteomics, and imaging mass spectrometry, which have significantly impacted neuronal biomarker research. By analyzing the complex protein interactions and alterations that occur in the injured brain, neuroproteomics provides valuable insights into the pathophysiological mechanisms underlying neurotrauma. This review explores how such insights can be harnessed to advance personalized medicine (PM) approaches, tailoring treatments based on individual patient profiles. Additionally, we highlight the potential future prospects of neuroproteomics, such as identifying novel biomarkers and developing targeted therapies by employing artificial intelligence (AI) and machine learning (ML). By shedding light on neurotrauma’s current state and future directions, this review aims to stimulate further research and collaboration in this promising and transformative field

Deep Learning for Detection and Segmentation in High-Content Microscopy Images

High-content microscopy led to many advances in biology and medicine. This fast emerging technology is transforming cell biology into a big data driven science. Computer vision methods are used to automate the analysis of microscopy image data. In recent years, deep learning became popular and had major success in computer vision. Most of the available methods are developed to process natural images. Compared to natural images, microscopy images pose domain specific challenges such as small training datasets, clustered objects, and class imbalance. In this thesis, new deep learning methods for object detection and cell segmentation in microscopy images are introduced. For particle detection in fluorescence microscopy images, a deep learning method based on a domain-adapted Deconvolution Network is presented. In addition, a method for mitotic cell detection in heterogeneous histopathology images is proposed, which combines a deep residual network with Hough voting. The method is used for grading of whole-slide histology images of breast carcinoma. Moreover, a method for both particle detection and cell detection based on object centroids is introduced, which is trainable end-to-end. It comprises a novel Centroid Proposal Network, a layer for ensembling detection hypotheses over image scales and anchors, an anchor regularization scheme which favours prior anchors over regressed locations, and an improved algorithm for Non-Maximum Suppression. Furthermore, a novel loss function based on Normalized Mutual Information is proposed which can cope with strong class imbalance and is derived within a Bayesian framework. For cell segmentation, a deep neural network with increased receptive field to capture rich semantic information is introduced. Moreover, a deep neural network which combines both paradigms of multi-scale feature aggregation of Convolutional Neural Networks and iterative refinement of Recurrent Neural Networks is proposed. To increase the robustness of the training and improve segmentation, a novel focal loss function is presented. In addition, a framework for black-box hyperparameter optimization for biomedical image analysis pipelines is proposed. The framework has a modular architecture that separates hyperparameter sampling and hyperparameter optimization. A visualization of the loss function based on infimum projections is suggested to obtain further insights into the optimization problem. Also, a transfer learning approach is presented, which uses only one color channel for pre-training and performs fine-tuning on more color channels. Furthermore, an approach for unsupervised domain adaptation for histopathological slides is presented. Finally, Galaxy Image Analysis is presented, a platform for web-based microscopy image analysis. Galaxy Image Analysis workflows for cell segmentation in cell cultures, particle detection in mice brain tissue, and MALDI/H&E image registration have been developed. The proposed methods were applied to challenging synthetic as well as real microscopy image data from various microscopy modalities. It turned out that the proposed methods yield state-of-the-art or improved results. The methods were benchmarked in international image analysis challenges and used in various cooperation projects with biomedical researchers

Multivariate calibration approach for quantitative determination of cell-line cross contamination by intact cell mass spectrometry and artificial neural networks

Cross-contamination of eukaryotic cell lines used in biomedical research represents a highly relevant problem. Analysis of repetitive DNA sequences, such as Short Tandem Repeats (STR), or Simple Sequence Repeats (SSR), is a widely accepted, simple, and commercially available technique to authenticate cell lines. However, it provides only qualitative information that depends on the extent of reference databases for interpretation. In this work, we developed and validated a rapid and routinely applicable method for evaluation of cell culture cross-contamination levels based on mass spectrometric fingerprints of intact mammalian cells coupled with artificial neural networks (ANNs). We used human embryonic stem cells (hESCs) contaminated by either mouse embryonic stem cells (mESCs) or mouse embryonic fibroblasts (MEFs) as a model. We determined the contamination level using a mass spectra database of known calibration mixtures that served as training input for an ANN. The ANN was then capable of correct quantification of the level of contamination of hESCs by mESCs or MEFs. We demonstrate that MS analysis, when linked to proper mathematical instruments, is a tangible tool for unraveling and quantifying heterogeneity in cell cultures. The analysis is applicable in routine scenarios for cell authentication and/or cell phenotyping in general

Pancreatic Cancer - Early Detection, Prognostic Factors, and Treatment

Background: Pancreatic cancer is the fourth leading cause of cancer-related death. Only about 6% of patients are alive 5 years after diagnosis. One reason for this low survival rate is that most patients are diagnosed at a late stage, when the tumor has spread to surrounding tissues or distant organs. Less than 20% of cases are diagnosed at an early stage that allows them to undergo potentially curative surgery. However, even for patients with a tumor that has been surgically removed, local and systemic recurrence is common and the median survival is only 17-23 months. This underscores the importance to identify factors that can predict postresection survival. With technical advances and centralization of care, pancreatic surgery has become a safe procedure. The future optimal treatment for pancreatic cancer is dependent on increased understanding of tumor biology and development of individualized and systemic treatment. Previous experimental studies have reported that mucins, especially the MUC4 mucin, may confer resistance to the chemotherapeutic agent gemcitabine and may serve as targets for the development of novel types of intervention. Aim: The aim of the thesis was to investigate strategies to improve management of pancreatic cancer, with special reference to early detection, prognostic factors, and treatment. Methods: In paper I, 27 prospectively collected serum samples from resectable pancreatic cancer (n=9), benign pancreatic disease (n=9), and healthy controls (n=9) were analyzed by high definition mass spectrometry (HDMSE). In paper II, an artificial neural network (ANN) model was constructed on 84 pancreatic cancer patients undergoing surgical resection. In paper III, we investigated the effects of transition from a low- to a high volume-center for pancreaticoduodenectomy in 221 patients. In paper IV, the grade of concordance in terms of MUC4 expression was examined in 17 tissue sections from primary pancreatic cancer and matched lymph node metastases. In paper V, pancreatic xenograft tumors were generated in 15 immunodeficient mice by subcutaneous injection of MUC4+ human pancreatic cancer cell lines; Capan-1, HPAF-II, or CD18/HPAF. In paper VI, a 76-member combined epigenetics and phosphatase small-molecule inhibitor library was screened against Capan-1 (MUC4+) and Panc-1 (MUC4-) cells, followed by high content screening of protein expression. Results/Conclusion: 134 differentially expressed serum proteins were identified, of which 40 proteins showed a significant up-regulation in the pancreatic cancer group. Pancreatic disease link associations could be made for BAZ2A, CDK13, DAPK1, DST, EXOSC3, INHBE, KAT2B, KIF20B, SMC1B, and SPAG5, by pathway network linkages to p53, the most frequently altered tumor suppressor in pancreatic cancer (I). An ANN survival model was developed, identifying 7 risk factors. The C-index for the model was 0.79, and it performed significantly better than the Cox regression (II). We experienced improved surgical results for pancreaticoduodenectomy after the transition to a high-volume center (≥25 procedures/year), including decreased operative duration, blood loss, hemorrhagic complications, reoperations, and hospital stay. There was also a tendency toward reduced operative mortality, from 4% to 0% (III). MUC4 positivity was detected in most primary pancreatic cancer tissues, as well as in matched metastatic lymph nodes (15/17 vs. 14/17), with a high concordance level (82%) (IV). The tumor incidence was 100% in the xenograft model. The median MUC4 count was found to be highest in Capan-1 tumors. α-SMA and collagen extent were also highest in Capan-1 tumors (V). Apicidin (a histone deacetylase inhibitor) had potent antiproliferative activity against Capan-1 cells and significantly reduced the expression of MUC4 and its transcription factor HNF4α. The combined treatment of apicidin and gemcitabine synergistically inhibited growth of Capan-1 cells (VI)

Lung Disease Classification using Dense Alex Net Framework with Contrast Normalisation and Five-Fold Geometric Transformation

lung disease is one of the leading causes of death worldwide. Most cases of lung diseases are found when the disease is in an advanced stage. Therefore, the development of systems and methods that begin to diagnose quickly and prematurely plays a vital role in today's world. Currently, in detecting differences in lung cancer, an accurate diagnosis of cancer types is needed. However, improving the accuracy and reducing training time of the diagnosis remains a challenge. In this study, we have developed an automated classification scheme for lung cancer presented in histopathological images using a dense Alex Net framework. The proposed methodology carries out several phases includes pre-processing, contrast normalization, data augmentation and classification. Initially, the pre-processing step is accompanied to diminish the noisy contents present in the image. Contrast normalization has been explored to maintain the same illumination factor among histopathological lung images next to pre-processing. Afterwards, data augmentation phase has been carried out to enhance the dataset further to avoid over-fitting problems. Finally, the Dense Alex Net is utilized for classification that comprises five convolutional layers, one multi-scale convolution layer, and three fully connected layers. In evaluation experiments, the proposed approach was trained using our original database to provide rich and meaningful features. The accuracy attained by the proposed methodology is93%, which is maximum compared with the existing algorithm