Modeling and Analyzing of Breast Tumor Deterioration Process with Petri Nets and Logistic Regression

It is important to understand the process of cancer cell metastasis and some cancer characteristics that increase disease risk. Because the occurrence of the disease is caused by many factors, and the pathogenesis process is also complicated. It is necessary to use interpretable and visual modeling methods to characterize this complex process. Machine learning techniques have demonstrated extraordinary capabilities in identifying models and extracting patterns from data to improve medical prognostic decisions. However, in most cases, it is unexplainable. Using formal methods to model can ensure the correctness and understandability of prediction decisions in a certain extent, and can well visualize the analysis process. Coloured Petri Nets (CPN) is a powerful formal model. This paper presents a modeling approach with CPN and machine learning in breast cancer, which can visualize the process of cancer cell metastasis and the impact of cell characteristics on the risk of disease. By evaluating the performance of several common machine learning algorithms, we finally choose the logistic regression algorithm to analyze the data, and integrate the obtained prediction model into the CPN model. Our method allows us to understand the relations among the cancer cell metastasis and clearly see the quantitative prediction results

Regularisoitu riippuvuuksien mallintaminen geeniekpressio- ja metabolomiikkadatan välillä metabolian säätelyn tutkimuksessa

Fusing different high-throughput data sources is an effective way to reveal functions of unknown genes, as well as regulatory relationships between biological components such as genes and metabolites. Dependencies between biological components functioning in the different layers of biological regulation can be investigated using canonical correlation analysis (CCA). However, the properties of the high-throughput bioinformatics data induce many challenges to data analysis: the sample size is often insufficient compared to the dimensionality of the data, and the data pose multi-collinearity due to, for example, co-expressed and co-regulated genes. Therefore, a regularized version of classical CCA has been adopted. An alternative way of introducing regularization to statistical models is to perform Bayesian data analysis with suitable priors. In this thesis, the performance of a new variant of Bayesian CCA called gsCCA is compared to a classical ridge regression regularized CCA (rrCCA) in revealing relevant information shared between two high-throughput data sets. The gsCCA produces a partly similar regulatory effect as the classical CCA but, in addition, the gsCCA introduces a new type of regularization to the data covariance matrices. Both CCA methods are applied to gene expression and metabolic concentration measurements obtained from an oxidative-stress tolerant Arabidopsis thaliana ecotype Col-0, and an oxidative stress sensitive mutant rcd1 as time series under ozone exposure and in a control condition. The aim of this work is to reveal new regulatory mechanisms in the oxidative stress signalling in plants. For the both methods, rrCCA and gsCCA, the thesis illustrates their potential to reveal both already known and new regulatory mechanisms in Arabidopsis thaliana oxidative stress signalling.Bioinformatiikassa erityyppisten mittausaineistojen yhdistäminen on tehokas tapa selvittää tuntemattomien geenien toiminnallisuutta sekä säätelyvuorovaikutuksia eri biologisten komponenttien, kuten geenien ja metaboliittien, välillä. Riippuvuuksia eri biologisilla säätelytasoilla toimivien komponenttien välillä voidaan tutkia kanonisella korrelaatioanalyysilla (canonical correlation analysis, CCA). Bioinformatiikan tietoaineistot aiheuttavat kuitenkin monia haasteita data-analyysille: näytteiden määrä on usein riittämätön verrattuna aineiston piirteiden määrään, ja aineisto on multikollineaarista johtuen esim. yhdessä säädellyistä ja ilmentyvistä geeneistä. Tästä syystä usein käytetään regularisoitua versiota kanonisesta korrelaatioanalyysistä aineiston tilastolliseen analysointiin. Vaihtoehto regularisoidulle analyysille on bayesilainen lähestymistapa yhdessä sopivien priorioletuksien kanssa. Tässä diplomityössä tutkitaan ja vertaillaan uuden bayesilaisen CCA:n sekä klassisen harjanneregressio-regularisoidun CCA:n kykyä löytää oleellinen jaettu informaatio kahden bioinformatiikka-tietoaineiston välillä. Uuden bayesilaisen menetelmän nimi on ryhmittäin harva kanoninen korrelaatioanalyysi. Ryhmittäin harva CCA tuottaa samanlaisen regularisointivaikutuksen kuin harjanneregressio-CCA, mutta lisäksi uusi menetelmä regularisoi tietoaineistojen kovarianssimatriiseja uudella tavalla. Molempia CCA-menetelmiä sovelletaan geenien ilmentymisaineistoon ja metaboliittien konsentraatioaineistoon, jotka on mitattu Arabidopsis thaliana:n hapetus-stressiä sietävästä ekotyypistä Col-0 ja hapetus-stressille herkästä rcd1 mutantista aika-sarjana, sekä otsoni-altistuksessa että kontrolliolosuhteissa. Diplomityö havainnollistaa harjanneregressio-CCA:n ja ryhmittäin harvan CCA:n kykyä paljastaa jo tunnettuja ja mahdollisesti uusia säätelymekanismeja geenien ja metabolittien välillä kasvisolujen viestinnässä hapettavan stressin aikana

Applications of Artificial Intelligence in Medicine Practice

This book focuses on a variety of interdisciplinary perspectives concerning the theory and application of artificial intelligence (AI) in medicine, medically oriented human biology, and healthcare. The list of topics includes the application of AI in biomedicine and clinical medicine, machine learning-based decision support, robotic surgery, data analytics and mining, laboratory information systems, and usage of AI in medical education. Special attention is given to the practical aspect of a study. Hence, the inclusion of a clinical assessment of the usefulness and potential impact of the submitted work is strongly highlighted

Implementation planning for lung cancer screening in China.

Lung cancer is the leading cause of cancer-related deaths in China, with over 690 000 lung cancer deaths estimated in 2018. The mortality has increased about five-fold from the mid-1970s to the 2000s. Lung cancer low-dose computerized tomography (LDCT) screening in smokers was shown to improve survival in the US National Lung Screening Trial, and more recently in the European NELSON trial. However, although the predominant risk factor, smoking contributes to a lower fraction of lung cancers in China than in the UK and USA. Therefore, it is necessary to establish Chinese-specific screening strategies. There have been 23 associated programmes completed or still ongoing in China since the 1980s, mainly after 2000; and one has recently been planned. Generally, their entry criteria are not smoking-stringent. Most of the Chinese programmes have reported preliminary results only, which demonstrated a different high-risk subpopulation of lung cancer in China. Evidence concerning LDCT screening implementation is based on results of randomized controlled trials outside China. LDCT screening programmes combining tobacco control would produce more benefits. Population recruitment (e.g. risk-based selection), screening protocol, nodule management and cost-effectiveness are discussed in detail. In China, the high-risk subpopulation eligible for lung cancer screening has not as yet been confirmed, as all the risk parameters have not as yet been determined. Although evidence on best practice for implementation of lung cancer screening has been accumulating in other countries, further research in China is urgently required, as China is now facing a lung cancer epidemic

Evaluation of Risk Models and Biomarkers for the Optimization of Lung Cancer Screening

More deaths can be attributed to lung cancer, than to any other cancer type. Evidence collected over the last 10 years, from randomized trials in the USA and Europe, indicates that screening by means of low-dose computed tomography (LDCT) could reduce the number of lung cancer (LC) deaths by about 20%-24%. While these findings have led to the implementation of screening programs in the USA, South Korea and Poland, discussions on their optimal design and execution are still ongoing in various countries, including Germany. Optimizing screening means finding the right balance between mortality reduction and risks, harms, and monetary costs. LDCT-scans are expensive, expose participants to radiation and put them at risk for overdiagnosis, as well as at risk for unnecessary invasive and expensive confirmatory procedures triggered by false positive (FP) results. Minimizing the number of unnecessary screening and confirmatory examinations should be prioritized. While risk-based eligibility has been shown to best target candidates, questions regarding optimal screening frequency, accurate nodule evaluation, stop-screening criteria to reduce overdiagnosis, and the use of complementary non-invasive diagnostic methods, remain open. Statistical models and biomarkers have been developed to help answer these questions. However, there is limited evidence of their validity in data from screening contexts and populations other than those in which they were developed. The analyses presented in this thesis are based on data collected as part of the German Lung Cancer Screening Intervention (LUSI) trial in order to validate models that address the questions: 1) can candidates for biennial vs annual screening be identified on the basis of their LC risk? 2) can the number of FP test results be reduced by accurately estimating the malignancy of LDCT-detected nodules? 3) What was the extent of overdiagnosis in the LUSI trial and how does overdiagnosis risk relate to the age and remaining lifetime of participants? Additionally, blood samples from participants of the LUSI were measured to evaluate: 4) whether the well-validated diagnostic biomarker test EarlyCDT®-Lung is sensitive enough to detect tumors seen in LDCT images. The LCRAT+CT and Polynomial models predict LC risk based on subject characteristics and LDCT imaging findings. Results of this first external validation confirmed their ability to identify participants with LC detected within 1-2 years after first screening. Discrimination was higher compared to a criterion based on nodule size and, to a lesser degree, compared to a model based on smoking and subject characteristics (LCRAT). This suggested that while LDCT findings can enhance models, most of their performance can could be attributed to information on smoking. Skipping 50% of annual LDCT examinations (i.e., for participants with estimated risks <5th decile) would have caused <10% delayed diagnoses, indicating that candidates for biennial screening could be identified based on their predicted LC risks without compromising on early detection. Absolute risk estimates were, on average, below the observed LC rates, indicating poor calibration. Models developed using data from the Canadian screening study PanCan showed excellent ability to differentiate between tumors and non-malignant nodules seen on LDCT scans taken at first screening participation and to accurately predict absolute malignancy risk. However, they showed lower performance when applied on data of nodules detected in later rounds. In contrast, a model developed on data from the UKLS trial and models developed on data from clinical settings did not perform as well in any screening round. Excess incidence of screen-detected lung tumors, an estimator of overdiagnosis, was within the range of values reported by other trials after similar post-screening follow-up (ca. 5-6 years). Estimates of mean pre-clinical sojourn time (MPST) and LDCT detection sensitivity were obtained via mathematical modeling. The highest excess incidence and longest MPST estimates were found among adenocarcinomas. The proportion of tumors with long lead times predicted based on MPST estimates (e.g., 23% with lead times ≥8 years) suggested a substantial overdiagnosis risk for individuals with residual life expectancies shorter than these hypothetical lead times, for example for heavy smokers over the age of 75. The tumor autoantibody panel measured by EarlyCDT®-Lung, a test widely validated as a diagnostic tool in clinical settings and recently tested as a pre-screening tool in a large randomized Scottish trial (ECLS), was found to have insufficient sensitivity for the identification of lung tumors detected via LDCT and of participants with screen-detected pulmonary nodules for whom more invasive diagnostic procedures should be recommended. Overall, the findings presented in this thesis indicate that risk prediction models can help optimize LC screening by assigning participants to appropriate screening intervals, and by increasing the accuracy of nodule evaluation. However, there is a need for further external model validation and re-calibration. Additionally, while excess incidence can provide estimates of overdiagnosis risk at a population-level, a better approach would be to obtain model-based personalized estimates of tumor lead and residual lifetime. Better individualized decisions about whether to start or stop screening could be taken on the basis of the relationship between these estimates and the risk of overdiagnosis. Finally, although there is evidence for the potential of biomarkers to complement LC screening, the so far most promising candidate (EarlyCDT®-Lung) cannot be recommended as a pre-screening tool given its poor sensitivity for the identification of lung tumors detected via LDCT. In conclusion, while steps have been taken in the right direction, more research is required in order to answer all open questions regarding the optimal design of lung cancer screening programs

Canada's Residential Schools: The Legacy

The Final Report of the Truth and Reconciliation Comission of Canada Volume

Diagnostic Significance of Exosomal miRNAs in the Plasma of Breast Cancer Patients

Poster Session AbstractsBackground and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for 25% (up-regulation) and 15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis.link_to_OA_fulltex

Fetal Alcohol Spectrum Disorder : circles of healing, transformation and reconciliation, Ke-ge-na-thee-tum-we-in

The Ph.D. dissertation encompasses an interdisciplinary study exploring qualitative, holistic strategies for individuals with Fetal Alcohol Spectrum Disorder (FASD) in integrated areas of law, medicine, education, psychology and justice, through both inductive analysis of field research as well as through relevant documentary analysis, incorporating a global or comparative component. Compliance with Guidelines for Research Involving Aboriginal Peoples has been sustained through community partnerships with various First Nations and Métis Communities, Elders and Parents, as well as with an FASD Parental Advocacy Group, advised by a team of interdisciplinary researchers in the academy. Accordingly, emergent research protocols were co-constructed through ongoing collaboration with the various community partners. In Aboriginal research, it is essential not to parachute in and out of communities with the data, but rather to forge genuine, collaborative, long term partnerships, and to build capacity in those communities. The dissertation format approved by the Student Advisory Committee is Manuscript Style, a format approved by the University of Saskatchewan’s College of Graduate Studies and Research (formerly referred to as X-Format) similar to a self-edited book or collection of articles with introduction, sub-text, intra-text and general discussion to link the manuscripts. The various manuscripts comprising the present thesis include: 1.Framing the Research Anthology: A Vision Quest, Ékehohksimoht Ke-kiss-see Muya Section One situates the research style, process, approach, substance and rationale of the dissertation. It is largely situated within holistic Indigenous epistemologies, which may require a paradigm shift, in contrast to more bounded western world views. Interdisciplinary, holistic, community-based research on the topic of FASD, including a search for solutions, extends globally, across the lifespan, and across sectors. II. Indigenous Disadvantage and Despair, An Evaluation of Recent Strategies and Alternatives: Healing and Transformation, Pluralism and Reconciliation, Ne wah kuma ka tik Section Two explores historical and contextual factors leading to a high prevalence of FASD, as well as strategies to overcome disadvantage, including Reconciliation, Treaty Processes, and Research as Reconciliation. Local Narratives are privileged over Meta-narratives, to counter the power of global market forces usurping the sphere of family, community and culture. III. Disjunctures and Discontinuities in the Law of Mental Intent: FASD as a Site of Resistance and Transformation, Esquiskuit Section Three examines the disconnect between medical knowledge of FASD, on the one hand, and the Laws of Mental Intent, on the other, inspiring a search for a unified, integrated theory of mental disorder and criminal responsibility that takes into account modern neurocognitive conditions like FASD. Section Three further explores the present piecemeal and compartmentalized rules for fitness, responsibility, various levels of mental intent, and a resultant rationale, substance and process of law reform and systemic change. IV. FASD and Holistic Literacies: A Talking or Sharing Circle, Wa-sa-cam-e-be-ke-skue Section Four’s inductive themes comprise model practice guidelines for the gestalt of Literacy and FASD, derived from inductive analysis of qualitative data collected in the field research. The data was collected using Sharing Circles with Aboriginal Elders, Parents, and Mentors of Individuals with FASD; Conversational Interviews with Parents and Children with FASD; as well as Interviews and Focus Groups with various Professionals who support individuals with FASD and their Families. Special protocols were followed in creating and participating in the Indigenous Research, Sharing Circles and Conversational Interviews. Meta-paradigmatic analysis situates Indigenous Research Methodologies among emerging, multi-disciplinary, inductive methodologies suitable for understanding the infinite complexity of natural phenomena, such as FASD. V. Epilogue: An Honour Song, Kethou-ne-ka-mon Circles of healing, transformation and reconciliation heal wounds, reconcile differences, and transform paradigms of justice, health, education and governance, through the incorporation of models of equitable, holistic relationships with one another and with Mother Earth. Multidisciplinary and cross-cultural perspectives, dialogues between local and global, and particular and universal, become matrices to support new paradigms embodying broader reflections of reality