Patient Similarity Analysis with Longitudinal Health Data

Healthcare professionals have long envisioned using the enormous processing powers of computers to discover new facts and medical knowledge locked inside electronic health records. These vast medical archives contain time-resolved information about medical visits, tests and procedures, as well as outcomes, which together form individual patient journeys. By assessing the similarities among these journeys, it is possible to uncover clusters of common disease trajectories with shared health outcomes. The assignment of patient journeys to specific clusters may in turn serve as the basis for personalized outcome prediction and treatment selection. This procedure is a non-trivial computational problem, as it requires the comparison of patient data with multi-dimensional and multi-modal features that are captured at different times and resolutions. In this review, we provide a comprehensive overview of the tools and methods that are used in patient similarity analysis with longitudinal data and discuss its potential for improving clinical decision making

Combining Representation Learning with Tensor Factorization for Risk Factor Analysis - an application to Epilepsy and Alzheimer's disease

Existing studies consider Alzheimer's disease (AD) a comorbidity of epilepsy, but also recognize epilepsy to occur more frequently in patients with AD than those without. The goal of this paper is to understand the relationship between epilepsy and AD by studying causal relations among subgroups of epilepsy patients. We develop an approach combining representation learning with tensor factorization to provide an in-depth analysis of the risk factors among epilepsy patients for AD. An epilepsy-AD cohort of ~600,000 patients were extracted from Cerner Health Facts data (50M patients). Our experimental results not only suggested a causal relationship between epilepsy and later onset of AD ( p = 1.92e-51), but also identified five epilepsy subgroups with distinct phenotypic patterns leading to AD. While such findings are preliminary, the proposed method combining representation learning with tensor factorization seems to be an effective approach for risk factor analysis

Clinically Meaningful Comparisons Over Time: An Approach to Measuring Patient Similarity based on Subsequence Alignment

Longitudinal patient data has the potential to improve clinical risk stratification models for disease. However, chronic diseases that progress slowly over time are often heterogeneous in their clinical presentation. Patients may progress through disease stages at varying rates. This leads to pathophysiological misalignment over time, making it difficult to consistently compare patients in a clinically meaningful way. Furthermore, patients present clinically for the first time at different stages of disease. This eliminates the possibility of simply aligning patients based on their initial presentation. Finally, patient data may be sampled at different rates due to differences in schedules or missed visits. To address these challenges, we propose a robust measure of patient similarity based on subsequence alignment. Compared to global alignment techniques that do not account for pathophysiological misalignment, focusing on the most relevant subsequences allows for an accurate measure of similarity between patients. We demonstrate the utility of our approach in settings where longitudinal data, while useful, are limited and lack a clear temporal alignment for comparison. Applied to the task of stratifying patients for risk of progression to probable Alzheimer's Disease, our approach outperforms models that use only snapshot data (AUROC of 0.839 vs. 0.812) and models that use global alignment techniques (AUROC of 0.822). Our results support the hypothesis that patients' trajectories are useful for quantifying inter-patient similarities and that using subsequence matching and can help account for heterogeneity and misalignment in longitudinal data

From Brain Imaging to Graph Analysis: a study on ADNI's patient cohort

In this paper, we studied the association between the change of structural brain volumes to the potential development of Alzheimer's disease (AD). Using a simple abstraction technique, we converted regional cortical and subcortical volume differences over two time points for each study subject into a graph. We then obtained substructures of interest using a graph decomposition algorithm in order to extract pivotal nodes via multi-view feature selection. Intensive experiments using robust classification frameworks were conducted to evaluate the performance of using the brain substructures obtained under different thresholds. The results indicated that compact substructures acquired by examining the differences between patient groups were sufficient to discriminate between AD and healthy controls with an area under the receiver operating curve of 0.72

Integrative Analysis of Patient Health Records and Neuroimages via Memory-based Graph Convolutional Network

With the arrival of the big data era, more and more data are becoming readily available in various real-world applications and those data are usually highly heterogeneous. Taking computational medicine as an example, we have both Electronic Health Records (EHR) and medical images for each patient. For complicated diseases such as Parkinson's and Alzheimer's, both EHR and neuroimaging information are very important for disease understanding because they contain complementary aspects of the disease. However, EHR and neuroimage are completely different. So far the existing research has been mainly focusing on one of them. In this paper, we proposed a framework, Memory-Based Graph Convolution Network (MemGCN), to perform integrative analysis with such multi-modal data. Specifically, GCN is used to extract useful information from the patients' neuroimages. The information contained in the patient EHRs before the acquisition of each brain image is captured by a memory network because of its sequential nature. The information contained in each brain image is combined with the information read out from the memory network to infer the disease state at the image acquisition timestamp. To further enhance the analytical power of MemGCN, we also designed a multi-hop strategy that allows multiple reading and updating on the memory can be performed at each iteration. We conduct experiments using the patient data from the Parkinson's Progression Markers Initiative (PPMI) with the task of classification of Parkinson's Disease (PD) cases versus controls. We demonstrate that superior classification performance can be achieved with our proposed framework, comparing with existing approaches involving a single type of data

Integrating Hypertension Phenotype and Genotype with Hybrid Non-negative Matrix Factorization

Hypertension is a heterogeneous syndrome in need of improved subtyping using phenotypic and genetic measurements so that patients in different subtypes share similar pathophysiologic mechanisms and respond more uniformly to targeted treatments. Existing machine learning approaches often face challenges in integrating phenotype and genotype information and presenting to clinicians an interpretable model. We aim to provide informed patient stratification by introducing Hybrid Non-negative Matrix Factorization (HNMF) on phenotype and genotype matrices. HNMF simultaneously approximates the phenotypic and genetic matrices using different appropriate loss functions, and generates patient subtypes, phenotypic groups and genetic groups. Unlike previous methods, HNMF approximates phenotypic matrix under Frobenius loss, and genetic matrix under Kullback-Leibler (KL) loss. We propose an alternating projected gradient method to solve the approximation problem. Simulation shows HNMF converges fast and accurately to the true factor matrices. On real-world clinical dataset, we used the patient factor matrix as features to predict main cardiac mechanistic outcomes. We compared HNMF with six different models using phenotype or genotype features alone, with or without NMF, or using joint NMF with only one type of loss. HNMF significantly outperforms all comparison models. HNMF also reveals intuitive phenotype-genotype interactions that characterize cardiac abnormalities.Comment: fixed some presentation error

Uncovering Longitudinal Healthcare Utilization from Patient-Level Medical Claims Data

The objective of this study is to introduce methodology for studying longitudinal claims data observed at the patient level, with inference on the heterogeneity of healthcare utilization behaviors within large healthcare systems such as Medicaid. The proposed approach is model-based, allowing for visualization of longitudinal utilization behaviors using simple stochastic graphical networks. The approach is general, providing a framework for the study of other chronic conditions wherever longitudinal healthcare utilization data are available. Our methods are inspired by and applied to patient-level Medicaid claims for asthma-diagnosed children diagnosed observed over a period of five years, with a comparison of two neighboring states, Georgia and North Carolina

Multi-layer Trajectory Clustering: A Network Algorithm for Disease Subtyping

Many diseases display heterogeneity in clinical features and their progression, indicative of the existence of disease subtypes. Extracting patterns of disease variable progression for subtypes has tremendous application in medicine, for example, in early prognosis and personalized medical therapy. This work present a novel, data-driven, network-based Trajectory Clustering (TC) algorithm for identifying Parkinson's subtypes based on disease trajectory. Modeling patient-variable interactions as a bipartite network, TC first extracts communities of co-expressing disease variables at different stages of progression. Then, it identifies Parkinson's subtypes by clustering similar patient trajectories that are characterized by severity of disease variables through a multi-layer network. Determination of trajectory similarity accounts for direct overlaps between trajectories as well as second-order similarities, i.e., common overlap with a third set of trajectories. This work clusters trajectories across two types of layers: (a) temporal, and (b) ranges of independent outcome variable (representative of disease severity), both of which yield four distinct subtypes. The former subtypes exhibit differences in progression of disease domains (Cognitive, Mental Health etc.), whereas the latter subtypes exhibit different degrees of progression, i.e., some remain mild, whereas others show significant deterioration after 5 years. The TC approach is validated through statistical analyses and consistency of the identified subtypes with medical literature. This generalizable and robust method can easily be extended to other progressive multi-variate disease datasets, and can effectively assist in targeted subtype-specific treatment in the field of personalized medicine.Comment: 20 pages, 8 figure

Similarity-based Random Survival Forest

Predicting time-to-event outcomes in large databases can be a challenging but important task. One example of this is in predicting the time to a clinical outcome for patients in intensive care units (ICUs), which helps to support critical medical treatment decisions. In this context, the time to an event of interest could be, for example, survival time or time to recovery from a disease/ailment observed within the ICU. The massive health datasets generated from the uptake of Electronic Health Records (EHRs) are quite heterogeneous as patients can be quite dissimilar in their relationship between the feature vector and the outcome, adding more noise than information to prediction. In this paper, we propose a modified random forest method for survival data that identifies similar cases in an attempt to improve accuracy for predicting time-to-event outcomes; this methodology can be applied in various settings, including with ICU databases. We also introduce an adaptation of our methodology in the case of dependent censoring. Our proposed method is demonstrated in the Medical Information Mart for Intensive Care (MIMIC-III) database, and, in addition, we present properties of our methodology through a comprehensive simulation study. Introducing similarity to the random survival forest method indeed provides improved predictive accuracy compared to random survival forest alone across the various analyses we undertook

Learning-Based Cost Functions for 3D and 4D Multi-Surface Multi-Object Segmentation of Knee MRI: Data from the Osteoarthritis Initiative

A fully automated knee MRI segmentation method to study osteoarthritis (OA) was developed using a novel hierarchical set of random forests (RF) classifiers to learn the appearance of cartilage regions and their boundaries. A neighborhood approximation forest is used first to provide contextual feature to the second-level RF classifier that also considers local features and produces location-specific costs for the layered optimal graph image segmentation of multiple objects and surfaces (LOGISMOS) framework. Double echo steady state (DESS) MRIs used in this work originated from the Osteoarthritis Initiative (OAI) study. Trained on 34 MRIs with varying degrees of OA, the performance of the learning-based method tested on 108 MRIs showed a significant reduction in segmentation errors (\emph{p}$<$0.05) compared with the conventional gradient-based and single-stage RF-learned costs. The 3D LOGISMOS was extended to longitudinal-3D (4D) to simultaneously segment multiple follow-up visits of the same patient. As such, data from all time-points of the temporal sequence contribute information to a single optimal solution that utilizes both spatial 3D and temporal contexts. 4D LOGISMOS validation on 108 MRIs from baseline and 12 month follow-up scans of 54 patients showed a significant reduction in segmentation errors (\emph{p}$<$0.01) compared to 3D. Finally, the potential of 4D LOGISMOS was further explored on the same 54 patients using 5 annual follow-up scans demonstrating a significant improvement of measuring cartilage thickness (\emph{p}$<$0.01) compared to the sequential 3D approach.Comment: IEEE Transactions in Medical Imaging, 11 page