DERMA: A melanoma diagnosis platform based on collaborative multilabel analog reasoning

The number of melanoma cancer-related death has increased over the last few years due to the new solar habits. Early diagnosis has become the best prevention method. This work presents a melanoma diagnosis architecture based on the collaboration of several multilabel case-based reasoning subsystems called DERMA. The system has to face up several challenges that include data characterization, pattern matching, reliable diagnosis, and self-explanation capabilities. Experiments using subsystems specialized in confocal and dermoscopy images have provided promising results for helping experts to assess melanoma diagnosis

DERMA: A Melanoma Diagnosis Platform Based on Collaborative Multilabel Analog Reasoning

The number of melanoma cancer-related death has increased over the last few years due to the new solar habits. Early diagnosis has become the best prevention method. This work presents a melanoma diagnosis architecture based on the collaboration of several multilabel case-based reasoning subsystems called DERMA. The system has to face up several challenges that include data characterization, pattern matching, reliable diagnosis, and self-explanation capabilities. Experiments using subsystems specialized in confocal and dermoscopy images have provided promising results for helping experts to assess melanoma diagnosis

Ajuda al Diagnòstic de Càncer de Melanoma amb Raonament Analògic Multietiqueta

La mortalitat provocada pel càncer de melanoma ha augmentat en els últims anys a causa, principalment, dels nous hàbits d'exposició al sol. Atenent al criteri mèdic, el diagnòstic precoç s'ha convertit en el millor mètode de prevenció. No és però una tasca trivial ja que els experts del domini han de fer front a un problema caracteritzat per tenir un gran volum de dades, de format heterogeni i amb coneixement parcial. A partir d'aquestes necessitats es proposa la creació d'una eina de suport a la presa de decisions que sigui capaç d'ajudar els experts en melanoma en el seu diagnòstic. El sistema ha de fer front a diversos reptes plantejats, que inclouen la caracterització del domini, la identificació de patrons a les dades segons el criteri dels experts, la classificació de nous pacients i la capacitat d'explicar els pronòstics obtinguts. Aquestes fites s'han materialitzat en la plataforma DERMA, la qual està basada en la col•laboració de diversos subsistemes de raonament analògic multietiqueta. L'experimentació realitzada amb el sistema proposat utilitzant dades d'imatges confocals i dermatoscòpiques ha permès comprovar la fiabilitat del sistema. Els resultats obtinguts han estat validats pels experts en el diagnòstic del melanoma considerant-los positius.La mortalidad a causa del cáncer de melanoma ha aumentado en los últimos años debido, principalmente, a los nuevos hábitos de exposición al sol. Atendiendo al criterio médico, el diagnóstico precoz se ha convertido en el mejor método de prevención, pero no se trata de una tarea trivial puesto que los expertos del dominio deben hacer frente a un problema caracterizado por tener un gran volumen de datos, de formato heterogéneo y con conocimiento parcial. A partir de estas necesidades se propone la creación de una herramienta de ayuda a la toma de decisiones que sea capaz de ayudar a los expertos en melanoma en su diagnóstico. El sistema tiene que hacer frente a diversos retos planteados, que incluyen la caracterización del dominio, la identificación de patrones en los datos según el criterio médico, la clasificación de nuevos pacientes y la capacidad de explicar los pronósticos obtenidos. Estas metas se han materializado en la plataforma DERMA la cual está basada en la colaboración de varios subsistemas de razonamiento analógico multietiqueta. La experimentación realizada con el sistema propuesto utilizando datos de imágenes confocales y dermatoscópicas ha permitido verificar la fiabilidad del sistema. Los resultados obtenidos han sido validados por los expertos en el diagnóstico del melanoma considerándolos positivos.Mortality related to melanoma cancer has increased in recent years, mainly due to new habits of sun exposure. Considering the medical criteria, early diagnosis has become the best method of prevention but this is not trivial because experts are facing a problem characterized by a large volume of data, heterogeneous, and with partial knowledge. Based on these requirements we propose the creation of a decision support system that is able to assist experts in melanoma diagnosis. The system has to cope with various challenges, that include the characterization of the domain, the identification of data patterns attending to medical criteria, the classification of new patients, and the ability to explain predictions. These goals have been materialized in DERMA platform that is based on the collaboration of several analogical reasoning multi-label subsystems. The experiments conducted with the proposed system using confocal and dermoscopic images data have been allowed to ascertain the reliability of the system. The results have been validated by experts in diagnosis of melanoma considering it as positive

Methodologies of Legacy Clinical Decision Support System -A Review

Information technology playing a prominent role in the field of medical by incorporating the Clinical Decision Support System(CDSS) in their routine practices. CDSS is a computer based interactive program to assist the physician to make the right decision at the right time. Now a day's Clinical decision support system is a dynamic research area in the field of computer, but the lack of the knowledge of the understanding as well as the functioning of the system ,make the adoption slow by the physician and patient. The literature review of this paper will focus on the overview of legacy CDSS, the kind of methodologies and classifier employed to prepare such decision support system using a non-technical approach to the physician and the strategy- makers . This study will provide the scope of understanding the clinical decision support along with the gateway to physician ,policy-makers to develop and deploy the decision support system as a healthcare service to make the quick, agile and right decision. Future direction to handle the uncertainties along with the challenges of clinical decision support system are also enlightened in this study

Development of a simple artificial intelligence method to accurately subtype breast cancers based on gene expression barcodes

>Magister Scientiae - MScINTRODUCTION: Breast cancer is a highly heterogeneous disease. The complexity of achieving an accurate diagnosis and an effective treatment regimen lies within this heterogeneity. Subtypes of the disease are not simply molecular, i.e. hormone receptor over-expression or absence, but the tumour itself is heterogeneous in terms of tissue of origin, metastases, and histopathological variability. Accurate tumour classification vastly improves treatment decisions, patient outcomes and 5-year survival rates. Gene expression studies aided by transcriptomic technologies such as microarrays and next-generation sequencing (e.g. RNA-Sequencing) have aided oncology researcher and clinician understanding of the complex molecular portraits of malignant breast tumours. Mechanisms governing cancers, which include tumorigenesis, gene fusions, gene over-expression and suppression, cellular process and pathway involvementinvolvement, have been elucidated through comprehensive analyses of the cancer transcriptome. Over the past 20 years, gene expression signatures, discovered with both microarray and RNA-Seq have reached clinical and commercial application through the development of tests such as Mammaprint®, OncotypeDX®, and FoundationOne® CDx, all which focus on chemotherapy sensitivity, prediction of cancer recurrence, and tumour mutational level. The Gene Expression Barcode (GExB) algorithm was developed to allow for easy interpretation and integration of microarray data through data normalization with frozen RMA (fRMA) preprocessing and conversion of relative gene expression to a sequence of 1's and 0's. Unfortunately, the algorithm has not yet been developed for RNA-Seq data. However, implementation of the GExB with feature-selection would contribute to a machine-learning based robust breast cancer and subtype classifier. METHODOLOGY: For microarray data, we applied the GExB algorithm to generate barcodes for normal breast and breast tumour samples. A two-class classifier for malignancy was developed through feature-selection on barcoded samples by selecting for genes with 85% stable absence or presence within a tissue type, and differentially stable between tissues. A multi-class feature-selection method was employed to identify genes with variable expression in one subtype, but 80% stable absence or presence in all other subtypes, i.e. 80% in n-1 subtypes. For RNA-Seq data, a barcoding method needed to be developed which could mimic the GExB algorithm for microarray data. A z-score-to-barcode method was implemented and differential gene expression analysis with selection of the top 100 genes as informative features for classification purposes. The accuracy and discriminatory capability of both microarray-based gene signatures and the RNA-Seq-based gene signatures was assessed through unsupervised and supervised machine-learning algorithms, i.e., K-means and Hierarchical clustering, as well as binary and multi-class Support Vector Machine (SVM) implementations. RESULTS: The GExB-FS method for microarray data yielded an 85-probe and 346-probe informative set for two-class and multi-class classifiers, respectively. The two-class classifier predicted samples as either normal or malignant with 100% accuracy and the multi-class classifier predicted molecular subtype with 96.5% accuracy with SVM. Combining RNA-Seq DE analysis for feature-selection with the z-score-to-barcode method, resulted in a two-class classifier for malignancy, and a multi-class classifier for normal-from-healthy, normal-adjacent-tumour (from cancer patients), and breast tumour samples with 100% accuracy. Most notably, a normal-adjacent-tumour gene expression signature emerged, which differentiated it from normal breast tissues in healthy individuals. CONCLUSION: A potentially novel method for microarray and RNA-Seq data transformation, feature selection and classifier development was established. The universal application of the microarray signatures and validity of the z-score-to-barcode method was proven with 95% accurate classification of RNA-Seq barcoded samples with a microarray discovered gene expression signature. The results from this comprehensive study into the discovery of robust gene expression signatures holds immense potential for further R&F towards implementation at the clinical endpoint, and translation to simpler and cost-effective laboratory methods such as qtPCR-based tests

Advanced Computational Methods for Oncological Image Analysis

[Cancer is the second most common cause of death worldwide and encompasses highly variable clinical and biological scenarios. Some of the current clinical challenges are (i) early diagnosis of the disease and (ii) precision medicine, which allows for treatments targeted to specific clinical cases. The ultimate goal is to optimize the clinical workflow by combining accurate diagnosis with the most suitable therapies. Toward this, large-scale machine learning research can define associations among clinical, imaging, and multi-omics studies, making it possible to provide reliable diagnostic and prognostic biomarkers for precision oncology. Such reliable computer-assisted methods (i.e., artificial intelligence) together with clinicians’ unique knowledge can be used to properly handle typical issues in evaluation/quantification procedures (i.e., operator dependence and time-consuming tasks). These technical advances can significantly improve result repeatability in disease diagnosis and guide toward appropriate cancer care. Indeed, the need to apply machine learning and computational intelligence techniques has steadily increased to effectively perform image processing operations—such as segmentation, co-registration, classification, and dimensionality reduction—and multi-omics data integration.

Deep Learning in Medical Image Analysis

The accelerating power of deep learning in diagnosing diseases will empower physicians and speed up decision making in clinical environments. Applications of modern medical instruments and digitalization of medical care have generated enormous amounts of medical images in recent years. In this big data arena, new deep learning methods and computational models for efficient data processing, analysis, and modeling of the generated data are crucially important for clinical applications and understanding the underlying biological process. This book presents and highlights novel algorithms, architectures, techniques, and applications of deep learning for medical image analysis

The immune microenvironment in mantle cell lymphoma : Targeted liquid and spatial proteomic analyses

The complex interplay of the tumour and immune cells affects tumour growth, progression, and response to treatment. Restorationof effective immune response forms the basis of onco-immunology, which further enabled the development of immunotherapy. Inthe era of precision medicine, pin-pointing patient biological heterogeneity especially in relation to patient-specific immunemicroenvironment is a necessity for the discovery of novel biomarkers and for development of patient stratification tools for targetedtherapeutics. Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell lymphoma with poor survival and high relapserates. Previous investigations of MCL have largely focused on the tumour itself and explorations of the immune microenvironmenthave been limited. This thesis and the included five papers, investigates multiple aspects of the immune microenvironment withrespect to proteomic analysis performed on tissue and liquid biopsies of diagnostic and relapsed/refractory (R/R) MCL cohorts.Analyses based on liquid biopsies (serum) in particular are relevant for aggressive cases such as in relapse, where invasiveprocedures for extracting tissues is not recommended. Thus, paper I-II probes the possibility of using serum for treatment andoutcome-associated biomarker discovery in R/R MCL, using a targeted affinity-based protein microarray platform quantifyingimmune-regulatory and tumor-secretory proteins in sera. Analysis performed in paper I using pre-treatment samples, identifies 11-plex biomarker signature (RIS – relapsed immune signature) associated with overall survival. Further integration of RIS with mantlecell lymphoma international prognostic index (MIPI) led to the development of MIPIris index for the stratification of R/R MCL intothree risk groups. Moreover, longitudinal analysis can be important in understanding how patient respond to treatment and thiscan further guide therapeutic interventions. Thus, paper II is a follow-up study wherein longitudinal analyses was performed onpaired samples collected at pre-treatment (baseline) and after three months of chemo-immunotherapy (on-treatment). We showhow genetic aberrations can influence systemic profiles and thus integrating genetic information can be crucial for treatmentselection. Furthermore, we observe that the inter-patient heterogeneity associated with absolute values can be circumvented byusing velocity of change to capture general changes over time in groups of patients. Thus, using velocity of change in serumproteins between pre- and on-treatment samples identified response biomarkers associated with minimal residual disease andprogression. While exploratory analysis using high dimensional omics-based data can be important for accelerating discovery,translating such information for clinical utility is a necessity. Thus, in paper III, we show how serum quantification can be usedcomplementary tissue-identified prognostic biomarkers and this can enable faster clinical implementation. Presence of CD163+M2-like macrophages has shown to be associated with poor outcome in MCL tissues. We show that higher expression of sCD163levels in sera quantified using ELISA, is also associated with poor outcome in diagnostic and relapsed MCL. Furthermore, wesuggest a cut-off for sCD163 levels that can be used for clinical utility. Further exploration of the dynamic interplay of tumourimmunemicroenvironment is now possible using spatial resolved omics for tissue-based analysis. Thus, in paper IV and V, weanalyse cell-type specific proteomic data collected from tumour and immune cells using GeoMx™ digital spatial profiler. In paperIV, we show that presence as well as spatial localization of CD163+ macrophage with respect to tumour regions impactsmacrophage phenotypic profiles. Further modulation in the profile of surrounding tumour and T-cells is observed whenmacrophages are present in the vicinity. Based on this analysis, we suggest MAPK pathway as a potential therapeutic target intumours with CD163+ macrophages. Immune composition can be defined not just by the type of cells, but also with respect tofrequency and spatial localization and this is explored in paper V with respect to T-cell subtypes. Thus, in paper V, we optimizeda workflow of multiplexed immunofluorescence image segmentation that allowed us to extract cell metrics for four subtypes ofCD3+ T-cells. Using this data, we show that higher infiltration of T-cells is associated with a positive outcome in MCL. Moreover,by combining image derived metrics to cell specific spatial omics data, we were able to identify immunosuppressivemicroenvironment associated with highly infiltrated tumours and suggests new potential targets of immunotherapy with respect toIDO1, GITR and STING. In conclusion, this thesis explores systemic and tumor-associated immune microenvironment in MCL, fordefining patient heterogeneity, developing methods of patient stratification and for identifying novel and actionable biomarkers

Interpretable deep neural networks for more accurate predictive genomics and genome-wide association studies

Genome-wide association studies (GWAS) and predictive genomics have become increasingly important in genetics research over the past decade. GWAS involves the analysis of the entire genome of a large group of individuals to identify genetic variants associated with a particular trait or disease. Predictive genomics combines information from multiple genetic variants to predict the polygenic risk score (PRS) of an individual for developing a disease. Machine learning is a branch of artificial intelligence that has revolutionized various fields of study, including computer vision, natural language processing, and robotics. Machine learning focuses on developing algorithms and models that enable computers to learn from data and make predictions or decisions without being explicitly programmed. Deep learning is a subset of machine learning that uses deep neural networks to recognize patterns and relationships. In this dissertation, we first compared various machine learning and statistical models for estimating breast cancer PRS. A deep neural network (DNN) was found to be the most effective, outperforming other techniques such as BLUP, BayesA, and LDpred. In the test cohort with 50% prevalence, the receiver operating characteristic curves area under the curves (ROC AUCs) were 67.4% for DNN, 64.2% for BLUP, 64.5% for BayesA, and 62.4% for LDpred. While BLUP, BayesA, and LDpred generated PRS that followed a normal distribution in the case population, the PRS generated by DNN followed a bimodal distribution. This allowed DNN to achieve a recall of 18.8% at 90% precision in the test cohort, which extrapolates to 65.4% recall at 20% precision in a general population. Interpretation of the DNN model identified significant variants that were previously overlooked by GWAS, highlighting their importance in predicting breast cancer risk. We then developed a linearizing neural network architecture (LINA) that provided first-order and second-order interpretations on both the instance-wise and model-wise levels, addressing the challenge of interpretability in neural networks. LINA outperformed other algorithms in providing accurate and versatile model interpretation, as demonstrated in synthetic datasets and real-world predictive genomics applications, by identifying salient features and feature interactions used for predictions. Finally, it has been observed that many complex diseases are related to each other through common genetic factors, such as pleiotropy or shared etiology. We hypothesized that this genetic overlap can be used to improve the accuracy of polygenic risk scores (PRS) for multiple diseases simultaneously. To test this hypothesis, we propose an interpretable multi-task learning approach based on the LINA architecture. We found that the parallel estimation of PRS for 17 prevalent cancers using a pan-cancer MTL model was generally more accurate than independent estimations for individual cancers using comparable single-task learning models. Similar performance improvements were observed for 60 prevalent non-cancer diseases in a pan-disease MTL model. Interpretation of the MTL models revealed significant genetic correlations between important sets of single nucleotide polymorphisms, suggesting that there is a well-connected network of diseases with a shared genetic basis