Causal Pattern Mining in Highly Heterogeneous and Temporal EHRs Data

University of Minnesota Ph.D. dissertation. March 2017. Major: Computer Science. Advisor: Vipin Kumar. 1 computer file (PDF); ix, 112 pages.The World Health Organization (WHO) estimates that the total healthcare spending in the U.S. is around 18\% of its GDP for the year 2011. Even with such a high per-capita expenditure, the quality of healthcare in U.S. lags behind as compared to the healthcare in other industrialized countries. This inefficient state of the U.S. healthcare system is attributed to the current Fee-for-service (FFS) model. Under the FFS model, healthcare providers (doctors, hospitals) receive payments for every hospital visit or service rendered. The lack of coordination between the service providers and patient outcomes, leads to an increase in the costs associated with the healthcare management, as healthcare providers often recommend expensive treatments. Several legislations have been approved in the recent past to improve the overall U.S. healthcare management while simultaneously reducing the associated costs. The HITECH Act, proposes to spend close to \$30 billion dollars on creating a nationwide repository of electronic Health Records (EHRs). Such a repository would consist of patient attributes such as demographics, laboratories test results, vital information and diagnosis codes. It is hoped that this EHR repository will be a platform to improve care coordination between service providers and patients healthcare outcomes, reduce health disparities thereby improving the overall healthcare management system. Data collected and stored in the EHR (HITECH) and the need to improve care efficiency and outcome (ACT) would help to improve the current state of U.S. healthcare system. Data mining techniques in conjunction with EHRs can be used to develop novel clinical decision making tools, to analyze the prevalence and incidence of diseases and to evaluate the efficacy of existing clinical and surgical interventions. In this thesis we focus on two key aspects of EHR data, i.e. temporality and causation. This becomes more important considering that the temporal nature of EHRs data has not been fully exploited. Further, increasing amounts of clinical evidence suggest that temporal nature is important for the development of clinical decision making tools and techniques. Secondly, several research articles hint at the the presence of antiquated clinical guidelines which are still in practice. In this dissertation, we first describe EHR along with the following terminologies : temporality, causation and heterogeneity. Building on this, we then describe methodologies for extracting non-causal patterns in the absence of longitudinal data. Further, we describe methods to extract non-causal patterns in the presence of longitudinal data. We describe such methodologies in the context of Type-2 Diabetes Mellitus (T2DM). Furthermore, we describe techniques to extract simple and complex causal patterns from longitudinal data in the context of sepsis and T2DM. Finally, we conclude this dissertation, by providing a summary of our work along with future directions

Teaching deep learning causal effects improves predictive performance

Causal inference is a powerful statistical methodology for explanatory analysis and individualized treatment effect (ITE) estimation, a prominent causal inference task that has become a fundamental research problem. ITE estimation, when performed naively, tends to produce biased estimates. To obtain unbiased estimates, counterfactual information is needed, which is not directly observable from data. Based on mature domain knowledge, reliable traditional methods to estimate ITE exist. In recent years, neural networks have been widely used in clinical studies. Specifically, recurrent neural networks (RNN) have been applied to temporal Electronic Health Records (EHR) data analysis. However, RNNs are not guaranteed to automatically discover causal knowledge, correctly estimate counterfactual information, and thus correctly estimate the ITE. This lack of correct ITE estimates can hinder the performance of the model. In this work we study whether RNNs can be guided to correctly incorporate ITE-related knowledge and whether this improves predictive performance. Specifically, we first describe a Causal-Temporal Structure for temporal EHR data; then based on this structure, we estimate sequential ITE along the timeline, using sequential Propensity Score Matching (PSM); and finally, we propose a knowledge-guided neural network methodology to incorporate estimated ITE. We demonstrate on real-world and synthetic data (where the actual ITEs are known) that the proposed methodology can significantly improve the prediction performance of RNN.Comment: 9 pages, 8 figures, in the process of SDM 202

Impact of Terminology Mapping on Population Health Cohorts IMPaCt

Background and Objectives: The population health care delivery model uses phenotype algorithms in the electronic health record (EHR) system to identify patient cohorts targeted for clinical interventions such as laboratory tests, and procedures. The standard terminology used to identify disease cohorts may contribute to significant variation in error rates for patient inclusion or exclusion. The United States requires EHR systems to support two diagnosis terminologies, the International Classification of Disease (ICD) and the Systematized Nomenclature of Medicine (SNOMED). Terminology mapping enables the retrieval of diagnosis data using either terminology. There are no standards of practice by which to evaluate and report the operational characteristics of ICD and SNOMED value sets used to select patient groups for population health interventions. Establishing a best practice for terminology selection is a step forward in ensuring that the right patients receive the right intervention at the right time. The research question is, “How does the diagnosis retrieval terminology (ICD vs SNOMED) and terminology map maintenance impact population health cohorts?” Aim 1 and 2 explore this question, and Aim 3 informs practice and policy for population health programs. Methods Aim 1: Quantify impact of terminology choice (ICD vs SNOMED) ICD and SNOMED phenotype algorithms for diabetes, chronic kidney disease (CKD), and heart failure were developed using matched sets of codes from the Value Set Authority Center. The performance of the diagnosis-only phenotypes was compared to published reference standard that included diagnosis codes, laboratory results, procedures, and medications. Aim 2: Measure terminology maintenance impact on SNOMED cohorts For each disease state, the performance of a single SNOMED algorithm before and after terminology updates was evaluated in comparison to a reference standard to identify and quantify cohort changes introduced by terminology maintenance. Aim 3: Recommend methods for improving population health interventions The socio-technical model for studying health information technology was used to inform best practice for the use of population health interventions. Results Aim 1: ICD-10 value sets had better sensitivity than SNOMED for diabetes (.829, .662) and CKD (.242, .225) (N=201,713, p Aim 2: Following terminology maintenance the SNOMED algorithm for diabetes increased in sensitivity from (.662 to .683 (p Aim 3: Based on observed social and technical challenges to population health programs, including and in addition to the development and measurement of phenotypes, a practical method was proposed for population health intervention development and reporting

Discovery of Type 2 Diabetes Trajectories from Electronic Health Records

University of Minnesota Ph.D. dissertation. September 2020. Major: Health Informatics. Advisor: Gyorgy Simon. 1 computer file (PDF); xiii, 110 pages.Type 2 diabetes (T2D) is one of the fastest growing public health concerns in the United States. There were 30.3 million patients (9.4% of the US populations) suffering from diabetes in 2015. Diabetes, which is the seventh leading cause of death in the United States, is known to be a non-reversible (incurable) chronic disease, leading to severe complications, including chronic kidney disease, amputation, blindness, and various cardiac and vascular diseases. Early identification of patients at high risk is regarded as the most effective clinical tool to prevent or delay the development of diabetes, allowing patients to change their life style or to receive medication earlier. In turn, these interventions can help decrease the risk of diabetes by 30-60%. Many studies have been conducted aiming at the early identification of patients at high risk in the clinical settings. These studies typically only consider the patient's current state at the time of the assessment and do not fully utilize all available information such as patient's medical history. Past history is important. It has been shown that laboratory results and vital signs can differ between diabetic and non-diabetic patients as many as 15-20 years before the onset of diabetes. We have also shown in our study that the order in which patients develop diabetes-related comorbidities is predictive of their diabetes risk even after adjusting for the severity of the comorbidities. In this thesis, we develop multiple novel methods to discover T2D trajectories from Electronic Health Records (EHR). We define trajectory as an order of in which diseases developed. We aim to discover typical and atypical trajectories where typical trajectories represent predominant patterns of progressions and atypical trajectories refer to the rest of the trajectories. Revealing trajectories can allow us to divide patients into subpopulations that can uncover the underlying etiology of diabetes. More importantly, by assessing the risk correctly and by a better understanding of the heterogeneity of diabetes, we can provide better care. Since data collected from EHR poses several challenges to directly identify trajectories from EHR data, we devise four specific studies to address the challenges: First, we propose a new knowledge-driven representation for clinical data mining, second, we demonstrate a method for estimating the onset time of slow-onset diseases from intermittently observable laboratory results in the specific context of T2D, third, we present a method to infer trajectories, the sequence of comorbidities potentially leading up to a particular disease of interest, and finally, we propose a novel method to discover multiple trajectories from EHR data. The patterns we discovered from above four studies address a clinical issue, are clinically verifiable and are amenable to deployment in practice to improve the quality of individual patient care towards promoting public health in the United States

Statin use and risk of new-onset diabetes : A meta-analysis of observational studies

Background and aims Meta-analyses of randomized control trials investigating the association between incident diabetes and statin use showed an increased risk of new-onset diabetes (NOD) from 9% to 13% associated with statins. However, short follow-up period, unpowered sample size, and lack of pre-specified diagnostic criteria for diabetes detection could be responsible of an underestimation of this risk. We conducted a meta-analysis of published observational studies to evaluate the association between statins use and risk of NOD. Methods and results PubMed, EMBASE and MEDLINE databases were searched from inception to June 30, 2016 for cohort and case\u2013control studies with risk of NOD in users vs nonusers, on 651000 subjects followed-up for 651 year. Two review authors assessed study eligibility and risk of bias and undertook data extraction independently. Pooled estimates were calculated by a random-effects model and between-study heterogeneity was tested and measured by I2 index. Furthermore, stratified analyses and the evaluation of publication bias were performed. Finally, the meta-analysis included 20 studies, 18 cohort and 2 case\u2013control studies. Overall, NOD risk was higher in statin users than nonusers (RR 1.44; 95% CI 1.31\u20131.58). High between-study heterogeneity (I2 = 97%) was found. Estimates for all single statins showed a class effect, from rosuvastatin (RR 1.61; 1.30\u20131.98) to simvastatin (RR 1.38; 1.19\u20131.61). Conclusions The present meta-analysis confirms and reinforces the evidence of a diabetogenic effect by statins utilization. These observations confirm the need of a rigorous monitoring of patients taking statins, in particular pre-diabetic patients or patients presenting with established risk factors for diabetes

Biomedical Literature Mining and Knowledge Discovery of Phenotyping Definitions

Indiana University-Purdue University Indianapolis (IUPUI)Phenotyping definitions are essential in cohort identification when conducting clinical research, but they become an obstacle when they are not readily available. Developing new definitions manually requires expert involvement that is labor-intensive, time-consuming, and unscalable. Moreover, automated approaches rely mostly on electronic health records’ data that suffer from bias, confounding, and incompleteness. Limited efforts established in utilizing text-mining and data-driven approaches to automate extraction and literature-based knowledge discovery of phenotyping definitions and to support their scalability. In this dissertation, we proposed a text-mining pipeline combining rule-based and machine-learning methods to automate retrieval, classification, and extraction of phenotyping definitions’ information from literature. To achieve this, we first developed an annotation guideline with ten dimensions to annotate sentences with evidence of phenotyping definitions' modalities, such as phenotypes and laboratories. Two annotators manually annotated a corpus of sentences (n=3,971) extracted from full-text observational studies’ methods sections (n=86). Percent and Kappa statistics showed high inter-annotator agreement on sentence-level annotations. Second, we constructed two validated text classifiers using our annotated corpora: abstract-level and full-text sentence-level. We applied the abstract-level classifier on a large-scale biomedical literature of over 20 million abstracts published between 1975 and 2018 to classify positive abstracts (n=459,406). After retrieving their full-texts (n=120,868), we extracted sentences from their methods sections and used the full-text sentence-level classifier to extract positive sentences (n=2,745,416). Third, we performed a literature-based discovery utilizing the positively classified sentences. Lexica-based methods were used to recognize medical concepts in these sentences (n=19,423). Co-occurrence and association methods were used to identify and rank phenotype candidates that are associated with a phenotype of interest. We derived 12,616,465 associations from our large-scale corpus. Our literature-based associations and large-scale corpus contribute in building new data-driven phenotyping definitions and expanding existing definitions with minimal expert involvement

Drug Repurposing

This book focuses on various aspects and applications of drug repurposing, the understanding of which is important for treating diseases. Due to the high costs and time associated with the new drug discovery process, the inclination toward drug repurposing is increasing for common as well as rare diseases. A major focus of this book is understanding the role of drug repurposing to develop drugs for infectious diseases, including antivirals, antibacterial and anticancer drugs, as well as immunotherapeutics

Integrative bioinformatics and graph-based methods for predicting adverse effects of developmental drugs

Adverse drug effects are complex phenomena that involve the interplay between drug molecules and their protein targets at various levels of biological organisation, from molecular to organismal. Many factors are known to contribute toward the safety profile of a drug, including the chemical properties of the drug molecule itself, the biological properties of drug targets and other proteins that are involved in pharmacodynamics and pharmacokinetics aspects of drug action, and the characteristics of the intended patient population. A multitude of scattered publicly available resources exist that cover these important aspects of drug activity. These include manually curated biological databases, high-throughput experimental results from gene expression and human genetics resources as well as drug labels and registered clinical trial records. This thesis proposes an integrated analysis of these disparate sources of information to help bridge the gap between the molecular and the clinical aspects of drug action. For example, to address the commonly held assumption that narrowly expressed proteins make safer drug targets, an integrative data-driven analysis was conducted to systematically investigate the relationship between the tissue expression profile of drug targets and the organs affected by clinically observed adverse drug reactions. Similarly, human genetics data were used extensively throughout the thesis to compare adverse symptoms induced by drug molecules with the phenotypes associated with the genes encoding their target proteins. One of the main outcomes of this thesis was the generation of a large knowledge graph, which incorporates diverse molecular and phenotypic data in a structured network format. To leverage the integrated information, two graph-based machine learning methods were developed to predict a wide range of adverse drug effects caused by approved and developmental therapies