Basic Science to Clinical Research: Segmentation of Ultrasound and Modelling in Clinical Informatics

The world of basic science is a world of minutia; it boils down to improving even a fraction of a percent over the baseline standard. It is a domain of peer reviewed fractions of seconds and the world of squeezing every last ounce of efficiency from a processor, a storage medium, or an algorithm. The field of health data is based on extracting knowledge from segments of data that may improve some clinical process or practice guideline to improve the time and quality of care. Clinical informatics and knowledge translation provide this information in order to reveal insights to the world of improving patient treatments, regimens, and overall outcomes. In my world of minutia, or basic science, the movement of blood served an integral role. The novel detection of sound reverberations map out the landscape for my research. I have applied my algorithms to the various anatomical structures of the heart and artery system. This serves as a basis for segmentation, active contouring, and shape priors. The algorithms presented, leverage novel applications in segmentation by using anatomical features of the heart for shape priors and the integration of optical flow models to improve tracking. The presented techniques show improvements over traditional methods in the estimation of left ventricular size and function, along with plaque estimation in the carotid artery. In my clinical world of data understanding, I have endeavoured to decipher trends in Alzheimer’s disease, Sepsis of hospital patients, and the burden of Melanoma using mathematical modelling methods. The use of decision trees, Markov models, and various clustering techniques provide insights into data sets that are otherwise hidden. Finally, I demonstrate how efficient data capture from providers can achieve rapid results and actionable information on patient medical records. This culminated in generating studies on the burden of illness and their associated costs. A selection of published works from my research in the world of basic sciences to clinical informatics has been included in this thesis to detail my transition. This is my journey from one contented realm to a turbulent one

Social analytics for health integration, intelligence, and monitoring

Nowadays, patient-generated social health data are abundant and Healthcare is changing from the authoritative provider-centric model to collaborative and patient-oriented care. The aim of this dissertation is to provide a Social Health Analytics framework to utilize social data to solve the interdisciplinary research challenges of Big Data Science and Health Informatics. Specific research issues and objectives are described below. The first objective is semantic integration of heterogeneous health data sources, which can vary from structured to unstructured and include patient-generated social data as well as authoritative data. An information seeker has to spend time selecting information from many websites and integrating it into a coherent mental model. An integrated health data model is designed to allow accommodating data features from different sources. The model utilizes semantic linked data for lightweight integration and allows a set of analytics and inferences over data sources. A prototype analytical and reasoning tool called “Social InfoButtons” that can be linked from existing EHR systems is developed to allow doctors to understand and take into consideration the behaviors, patterns or trends of patients’ healthcare practices during a patient’s care. The tool can also shed insights for public health officials to make better-informed policy decisions. The second objective is near-real time monitoring of disease outbreaks using social media. The research for epidemics detection based on search query terms entered by millions of users is limited by the fact that query terms are not easily accessible by non-affiliated researchers. Publically available Twitter data is exploited to develop the Epidemics Outbreak and Spread Detection System (EOSDS). EOSDS provides four visual analytics tools for monitoring epidemics, i.e., Instance Map, Distribution Map, Filter Map, and Sentiment Trend to investigate public health threats in space and time. The third objective is to capture, analyze and quantify public health concerns through sentiment classifications on Twitter data. For traditional public health surveillance systems, it is hard to detect and monitor health related concerns and changes in public attitudes to health-related issues, due to their expenses and significant time delays. A two-step sentiment classification model is built to measure the concern. In the first step, Personal tweets are distinguished from Non-Personal tweets. In the second step, Personal Negative tweets are further separated from Personal Non-Negative tweets. In the proposed classification, training data is labeled by an emotion-oriented, clue-based method, and three Machine Learning models are trained and tested. Measure of Concern (MOC) is computed based on the number of Personal Negative sentiment tweets. A timeline trend of the MOC is also generated to monitor public concern levels, which is important for health emergency resource allocations and policy making. The fourth objective is predicting medical condition incidence and progression trajectories by using patients’ self-reported data on PatientsLikeMe. Some medical conditions are correlated with each other to a measureable degree (“comorbidities”). A prediction model is provided to predict the comorbidities and rank future conditions by their likelihood and to predict the possible progression trajectories given an observed medical condition. The novel models for trajectory prediction of medical conditions are validated to cover the comorbidities reported in the medical literature

Atrial fibrillation and frailty: An observational cohort study using electronic healthcare records

Atrial fibrillation is common in older people, and is associated with increased mortality and stroke. Patients with atrial fibrillation/flutter (AF) also commonly have frailty, which is associated with increased risk of a range of further adverse clinical outcomes. However, there is a lack of evidence on the burden and management of AF in people with frailty. A study using the primary care electronic health records of 536,955 patients aged ≥65 years was conducted to investigate the burden of frailty and AF amongst older people, and their associations with clinical outcomes. A systematic review and meta-analysis was completed to establish the current knowledge base, and to inform the quantitative analyses. Baseline characteristics were described and compared between those with and without AF as well as by frailty category according to the electronic frailty index. Rates of all-cause mortality, stroke, bleeding (intracranial and gastrointestinal), transient ischaemic attack (TIA), and falls were calculated per 1000 person-years, and compared with the non-AF patient population. Cox proportional hazards modelling was used to determine unadjusted and adjusted risk for each clinical outcome and mortality, and presented as hazard ratios (HR) alongside 95% confidence intervals. The association between oral anticoagulation (OAC) prescription stratified by frailty category with clinical outcomes was investigated using Cox proportional hazards modelling. At baseline, 61,177 (11.4%) patients had AF. People with AF had a higher burden of frailty than those without (89.5% vs. 55.3%) and had higher rates of mortality, stroke, TIA and bleeding. Of patients with AF and eligible for OAC, it was prescribed in 53.1% (41.7% in robust, mild frailty 53.2%, moderate 55.6%, severe 53.4%). OAC was associated with a 19% reduction in all-cause mortality (HR 0.81, 95%CI 0.77-0.85) and 22% reduction in stroke (HR 0.78, 0.67-0.92). There was no statistically significant difference in rates of bleeding between those prescribed and not prescribed OAC. For the first time in a large representative cohort of older people, this study quantified the burden of AF and frailty, and their association with a range of clinical outcomes. This study found no evidence that OAC should be withheld on the basis of concomitant frailty

Artificial intelligence in digital pathology: a diagnostic test accuracy systematic review and meta-analysis

Ensuring diagnostic performance of AI models before clinical use is key to the safe and successful adoption of these technologies. Studies reporting AI applied to digital pathology images for diagnostic purposes have rapidly increased in number in recent years. The aim of this work is to provide an overview of the diagnostic accuracy of AI in digital pathology images from all areas of pathology. This systematic review and meta-analysis included diagnostic accuracy studies using any type of artificial intelligence applied to whole slide images (WSIs) in any disease type. The reference standard was diagnosis through histopathological assessment and / or immunohistochemistry. Searches were conducted in PubMed, EMBASE and CENTRAL in June 2022. We identified 2976 studies, of which 100 were included in the review and 48 in the full meta-analysis. Risk of bias and concerns of applicability were assessed using the QUADAS-2 tool. Data extraction was conducted by two investigators and meta-analysis was performed using a bivariate random effects model. 100 studies were identified for inclusion, equating to over 152,000 whole slide images (WSIs) and representing many disease types. Of these, 48 studies were included in the meta-analysis. These studies reported a mean sensitivity of 96.3% (CI 94.1-97.7) and mean specificity of 93.3% (CI 90.5-95.4) for AI. There was substantial heterogeneity in study design and all 100 studies identified for inclusion had at least one area at high or unclear risk of bias. This review provides a broad overview of AI performance across applications in whole slide imaging. However, there is huge variability in study design and available performance data, with details around the conduct of the study and make up of the datasets frequently missing. Overall, AI offers good accuracy when applied to WSIs but requires more rigorous evaluation of its performance.Comment: 26 pages, 5 figures, 8 tables + Supplementary material

Front-Line Physicians' Satisfaction with Information Systems in Hospitals

Day-to-day operations management in hospital units is difficult due to continuously varying situations, several actors involved and a vast number of information systems in use. The aim of this study was to describe front-line physicians' satisfaction with existing information systems needed to support the day-to-day operations management in hospitals. A cross-sectional survey was used and data chosen with stratified random sampling were collected in nine hospitals. Data were analyzed with descriptive and inferential statistical methods. The response rate was 65 % (n = 111). The physicians reported that information systems support their decision making to some extent, but they do not improve access to information nor are they tailored for physicians. The respondents also reported that they need to use several information systems to support decision making and that they would prefer one information system to access important information. Improved information access would better support physicians' decision making and has the potential to improve the quality of decisions and speed up the decision making process.Peer reviewe

Generating Reliable and Responsive Observational Evidence: Reducing Pre-analysis Bias

A growing body of evidence generated from observational data has demonstrated the potential to influence decision-making and improve patient outcomes. For observational evidence to be actionable, however, it must be generated reliably and in a timely manner. Large distributed observational data networks enable research on diverse patient populations at scale and develop new sound methods to improve reproducibility and robustness of real-world evidence. Nevertheless, the problems of generalizability, portability and scalability persist and compound. As analytical methods only partially address bias, reliable observational research (especially in networks) must address the bias at the design stage (i.e., pre-analysis bias) including the strategies for identifying patients of interest and defining comparators. This thesis synthesizes and enumerates a set of challenges to addressing pre-analysis bias in observational studies and presents mixed-methods approaches and informatics solutions for overcoming a number of those obstacles. We develop frameworks, methods and tools for scalable and reliable phenotyping including data source granularity estimation, comprehensive concept set selection, index date specification, and structured data-based patient review for phenotype evaluation. We cover the research on potential bias in the unexposed comparator definition including systematic background rates estimation and interpretation, and definition and evaluation of the unexposed comparator. We propose that the use of standardized approaches and methods as described in this thesis not only improves reliability but also increases responsiveness of observational evidence. To test this hypothesis, we designed and piloted a Data Consult Service - a service that generates new on-demand evidence at the bedside. We demonstrate that it is feasible to generate reliable evidence to address clinicians’ information needs in a robust and timely fashion and provide our analysis of the current limitations and future steps needed to scale such a service

Precision health approaches: ethical considerations for health data processing

This thesis provides insights and recommendations on some of the most crucial elements necessary for an effective, legally and ethically sound implementation of precision health approaches in the Swiss context (and beyond), specifically for precision medicine and precision public health. In this regard, this thesis recognizes the centrality of data in these two abovementioned domains, and the ethical and scientific imperative of ensuring the widespread and responsible sharing of high quality health data between the numerous stakeholders involved in healthcare, public health and associated research domains. It also recognizes the need to protect not only the interests of data subjects but also those of data processors. Indeed, it is only through a comprehensive assessment of the needs and expectations of each and every one regarding data sharing activities that sustainable solutions to known ethical and scientific conundrums can be devised and implemented. In addition, the included chapters in this thesis emphasize recommending solutions that could be convincingly applied to real world problems, with the ultimate objective of having a concrete impact on clinical and public health practice and policies, including research activities. Indeed, the strengths of this thesis reside in a careful and in-depth interdisciplinary assessment of the different issues at stake in precision health approaches, with the elaboration of the least disruptive solutions (as far as possible) and recommendations for an easy evaluation and subsequent adoption by relevant stakeholders active in these two domains. This thesis has three main objectives, namely (i) to investigate and identify factors influencing the processing of health data in the Swiss context and suggest some potential solutions and recommendations. A better understanding of these factors is paramount for an effective implementation of precision health approaches given their strong dependence on high quality and easily accessible health datasets; (ii) to identify and explore the ethical, legal and social issues (ELSI) of innovative participatory disease surveillance systems – also falling under precision health approaches – and how research ethics are coping within this field. In addition, this thesis aims to strengthen the ethical approaches currently used to cater for these ELSIs by providing a robust ethical framework; and lastly, (iii) to investigate how precision health approaches might not be able to achieve their social justice and health equity goals, if the impact of structural racism on these initiatives is not given due consideration. After a careful assessment, this thesis provides recommendations and potential actions that could help these precision health approaches adhere to their social justice and health equity goals. This thesis has investigated these three main objectives using both empirical and theoretical research methods. The empirical branch consists of systematic and scoping reviews, both adhering to the PRISMA guidelines, and two interview-based studies carried out with Swiss expert stakeholders. The theoretical branch consists of three chapters, each addressing important aspects concerning precision health approaches

COMPUTATIONAL PHENOTYPING AND DRUG REPURPOSING FROM ELECTRONIC MEDICAL RECORDS

Using electronic medical records (EMR) for research involves selecting cohorts and manipulating data for tasks like predictive analysis. Computational phenotyping for cohort characterization and stratification is becoming increasingly important for researchers to produce clinically relevant findings. There are significant amounts of time and effort devoted to manual chart abstraction by subject matter experts and researchers, which creates a large bottleneck for progress in clinical research. I focus on developing computational phenotyping pipelines, and I also focus on using EMR for drug repurposing in breast cancer. Drug repurposing is defined as the process of applying known drugs that are already on the market to new disease indications. Using EMR data for drug repurposing has the unique advantage of being able to observe a patient cohort over time and see drug effects on outcomes. In this dissertation, I present work on computational phenotyping and EMR-based drug repurposing. First, I use embedding models and foundational natural language processing methods to predict oral cancer risk with pathology notes. Second, I use natural language processing methods and transfer learning for breast cancer cohort selection and information extraction. Third, I present a pipeline for producing drug repurposing candidates from EMR and provide supporting evidence for predictions with biomedical literature and existing clinical trials.Doctor of Philosoph

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

Long-term mental health and quality of life in women with a history of breast cancer

This thesis focused on the long-term mental health and quality of life of breast cancer survivors, compared to women with no prior cancer. The first study was a systematic review of studies that assessed adverse mental health outcomes in women who had breast cancer and non-cancer controls. This found evidence suggestive of an increased risk of anxiety, depression, suicide, and neurocognitive and sexual dysfunctions in breast cancer survivors. The second study systematically summarised the lists of Read codes and clinical definitions used in previous studies of mental health-related outcomes in primary care databases of electronic health records in the UK. The results showed substantial heterogeneity across studies and informed the definition of the outcomes in this thesis. The third study used data from the UK Clinical Practice Research Datalink (CPRD) GOLD primary care database to quantify the risk of adverse mental health-related outcomes in 57,571 breast cancer survivors and 230,067 women with no previous cancer. Breast cancer survivorship was positively associated with anxiety, depression, fatigue, pain, sexual dysfunction, sleep disorder and being prescribed opioid analgesics, but there was no evidence of association with cognitive dysfunction or fatal and non-fatal self-harm. The fourth study included 353 breast cancer survivors and 252 women with no prior cancer who replied to questionnaires assessing quality of life and mental health. Compared to women with no prior cancer, breast cancer survivors had poorer quality of life in the domains of cognitive problems, sexual function, and fatigue, but no evidence of difference in negative feelings, positive feelings, pain, or social avoidance. Women with advanced-stage cancer at diagnosis, and/or prior receipt of chemotherapy, had poorer quality of life and mental health. In conclusion, breast cancer survivorship is associated with impaired quality of life and raised risk of adverse mental health-related outcomes, persisting well into the survivorship period