Comprehensive Immune Monitoring of Clinical Trials to Advance Human Immunotherapy.

The success of immunotherapy has led to a myriad of clinical trials accompanied by efforts to gain mechanistic insight and identify predictive signatures for personalization. However, many immune monitoring technologies face investigator bias, missing unanticipated cellular responses in limited clinical material. We present here a mass cytometry (CyTOF) workflow for standardized, systems-level biomarker discovery in immunotherapy trials. To broadly enumerate immune cell identity and activity, we established and extensively assessed a reference panel of 33 antibodies to cover major cell subsets, simultaneously quantifying activation and immune checkpoint molecules in a single assay. This assay enumerates ≥98% of peripheral immune cells with ≥4 positively identifying antigens. Robustness and reproducibility are demonstrated on multiple samples types, across two research centers and by orthogonal measurements. Using automated analysis, we identify stratifying immune signatures in bone marrow transplantation-associated graft-versus-host disease. Together, this validated workflow ensures comprehensive immunophenotypic analysis and data comparability and will accelerate biomarker discovery

Quantitative Phenotype Analysis to Identify, Validate and Compare Rat Disease Models

Introduction The laboratory rat has been widely used as an animal model in biomedical research. There are many strains exhibiting a wide variety of phenotypes. Capturing these phenotypes in a centralized database provides researchers with an easy method for choosing the appropriate strains for their studies. Current resources such as NBRP and PhysGen provided some preliminary work in rat phenotype databases. However, there are drawbacks in both projects: (1) small number of animals (6 rats) used by NBRP; (2) NBRP project is a one-time effort for each strain; (3) PhysGen web interface only enables queries within a single study – data comparison and integration not possible; (4) PhysGen lacks a data standardization process so that the measurement method, experimental condition, and age of rats used are hidden. Therefore, there is a need for a better data integration and visualization method in order to provide users with more insights about phenotype differences across rat strains. The Rat Genome Database (RGD) PhenoMiner tool has provided the first step in this effort by standardizing and integrating data from individual studies as well as NBRP and PhysGen. Methods Our work involved the following key steps: (1) we developed a meta-analysis pipeline to automatically integrate data from heterogeneous sources and to produce expected ranges (standardized phenotype ranges) for different strains, and different phenotypes under different experimental conditions; (2) we created tools to visualize expected ranges for individual strains and strain groups; (3) we clustered substrains into different sub-populations according to phenotype correlations. Results We developed a meta-analysis pipeline and an interactive web interface that summarizes and visualizes expected ranges produced from the meta-analysis pipeline. Automation of the pipeline allows for updates as additional data becomes available. The interactive web interface provides the researchers with a platform for identifying and validating expected ranges for a variety of quantitative phenotypes. In addition, we performed a preliminary cluster analysis that enables researchers to examine similarities of strains, substrains, and different sex or age groups of strains on a multi-dimensional scale by using multiple phenotype features. Conclusion The data resources and the data mining and visualization tools will promote an understanding of rat disease models, guide researchers to choose optimal strains for their research needs, and encourage data sharing from different research hubs. Such resources also help to promote research reproducibility. Data produced and interactive platforms created in this project will continue to provide a valuable resource for Translational Research efforts

Scale Stain: Multi-Resolution Feature Enhancement in Pathology Visualization

Digital whole-slide images of pathological tissue samples have recently become feasible for use within routine diagnostic practice. These gigapixel sized images enable pathologists to perform reviews using computer workstations instead of microscopes. Existing workstations visualize scanned images by providing a zoomable image space that reproduces the capabilities of the microscope. This paper presents a novel visualization approach that enables filtering of the scale-space according to color preference. The visualization method reveals diagnostically important patterns that are otherwise not visible. The paper demonstrates how this approach has been implemented into a fully functional prototype that lets the user navigate the visualization parameter space in real time. The prototype was evaluated for two common clinical tasks with eight pathologists in a within-subjects study. The data reveal that task efficiency increased by 15% using the prototype, with maintained accuracy. By analyzing behavioral strategies, it was possible to conclude that efficiency gain was caused by a reduction of the panning needed to perform systematic search of the images. The prototype system was well received by the pathologists who did not detect any risks that would hinder use in clinical routine

Pathway activity analysis of bulk and single-cell RNA-Seq data

Gene expression profiling can produce effective biomarkers that can provide additional information beyond other approaches for characterizing disease. While these approaches are typically performed on standard bulk RNA sequencing data, new methods for RNA sequencing of individual cells have allowed these approaches to be applied at the resolution of a single cell. As these methods enter the mainstream, there is an increased need for user-friendly software that allows researchers without experience in bioinformatics to apply these techniques. In this thesis, I have developed new, user-friendly data resources and software tools to allow researchers to use gene expression signatures in their own datasets. Specifically, I created the Single Cell Toolkit, a user-friendly and interactive toolkit for analyzing single-cell RNA sequencing data and used this toolkit to analyze the pathway activity levels in breast cancer cells before and after cancer therapy. Next, I created and validated a set of activated oncogenic growth factor receptor signatures in breast cancer, which revealed additional heterogeneity within public breast cancer cell line and patient sample RNA sequencing datasets. Finally, I created an R package for rapidly profiling TB samples using a set of 30 existing tuberculosis gene signatures. I applied this tool to look at pathway differences in a dataset of tuberculosis treatment failure samples. Taken together, the results of these studies serve as a set of user-friendly software tools and data sets that allow researchers to rapidly and consistently apply pathway activity methods across RNA sequencing samples

의학 연구에서의 과학적 증거의 활용을 위한 시각적 분석 시스템 디자인

학위논문(박사) -- 서울대학교대학원 : 공과대학 컴퓨터공학부, 2022. 8. 서진욱.Evidence-based medicine, "the conscientious, explicit, and judicious use of current best evidence in healthcare and medical research" [98], is one of the most widely accepted medical paradigms of modern times. Searching, reviewing, and synthesizing reliable and high-quality scientific evidence is the key step for the paradigm. However, despite the widespread use of the EBM paradigm, challenges remain in applying Evidence-based medicine protocols to medical research. One of the barriers to applying the best scientific evidence to medical research is the severe literature and clinical data overload that causes the evidence-based tasks to be tremendous time-consuming tasks that require vast human effort. In this dissertation, we aim to employ visual analytics approaches to address the challenges of searching and reviewing massive scientific evidence in medical research. To overcome the burden and facilitate handling scientific evidence in medical research, we conducted three design studies and implemented novel visual analytics systems for laborious evidence-based tasks. First, we designed PLOEM, a novel visual analytics system to aid evidence synthesis, an essential step in Evidence-Based medicine, and generate an Evidence Map in a standardized method. We conducted a case study with an oncologist with years of evidence-based medicine experience. In the second study, we conducted a preliminary survey with 76 medical doctors to derive the design requirements for a biomedical literature search. Based on the results, We designed EEEVis, an interactive visual analytic system for biomedical literature search tasks. The system enhances the PubMed search result with several bibliographic visualizations and PubTator annotations. We performed a user study to evaluate the designs with 24 medical doctors and presented the design guidelines and challenges for a biomedical literature search system design. The third study presents GeneVis, a visual analytics system to identify and analyze gene expression signatures across major cancer types. A task that cancer researchers utilize to discover biomarkers in precision medicine. We conducted four case studies with domain experts in oncology and genomics. The study results show that the system can facilitate the task and provide new insights from the data. Based on the three studies of this dissertation, we conclude that carefully designed visual analytics approaches can provide an enhanced understanding and support medical researchers for laborious evidence-based tasks in medical research.근거중심의학(Evidence-Based Medicine)이란 "임상 치료 및 의학 연구에서 현재 존재하는 최고의 증거를 양심적이고, 명백하며, 분별 있게 이용하는 방법론"이며 [98], 현대 의학에서 가장 널리 받아들여지는 의학 패러다임이다. 신뢰할 수 있는 고수준의 과학적 근거를 검색, 검토, 합성하는 것이야 말로 근거중심의학의 핵심이다. 하지만, 근거중심의학이 이미 광범위하게 사용되고 있음에도 불구하고, 의학 연구에 근거중심의학의 프로토콜을 실천하는 데에는 여전히 많은 어려움이 따른다. 의료 문헌 정보, 임상 정보 및 유전체학 정보까지 연구자가 검토해야 할 근거의 양은 방대하며 광범위하다. 또한 의학과 기술의 발전으로 인해 점차 더 빠른 속도로 늘어나고 있기에, 이를 모두 엄밀히 검토하기 위해서는 막대한 양의 시간과 인력이 있어야 한다. 본 논문은 시각적 분석 방법론을 접목하여 의학 연구에서 방대한 과학적 증거를 검색하고 검토할 시 발생하는 막대한 인적 자원의 과부하 문제를 완화하고자 한다. 이를 위하여 근거중심의학의 절차 중 특히 인력 소모가 막심한 절차들을 선정하고, 이러한 난관을 극복하고 보다 효율적이고 효과적으로 데이터에서 유의미한 정보를 도출할 수 있게끔 보조하는 세 가지 시각적 분석 시스템들을 구현하였으며, 각각의 시스템에 관한 디자인 연구를 수행하였다. 우선 첫 디자인 연구에서는 근거중심의학 연구에 있어 필수적 단계인 근거 합성 방법론의 하나인 근거 매핑(Evidence Mapping) 과정을 지원하기 위한 시각적 분석 시스템 PLOEM을 설계했다. 그리고 이를 검증하기 위해 다년간의 근거 기반 의료 경험이 있는 종양학자와 함께 사례 연구를 수행했다. 두 번째 디자인 연구에서는 의학 문헌 검색 시스템의 요구사항 분석을 위해 총 76명의 의사를 상대로 설문조사를 진행하였고, 이러한 분석을 바탕으로 대화형 시각적 분석 시스템인 EEEVis를 설계했다. 이 시스템은 여러 종의 서지 정보 시각화 인터페이스와 PubTator의 주석 정보를 활용하여 PubMed 검색 엔진의 검색 결과를 증강하는 시스템이며, 이를 평가하기 위해 총 24명의 의사와 함께 사용자 연구를 수행하였다. 이 연구 결과를 바탕으로 의학 문헌 검색 시스템에 대한 설계 지침과 과제를 제시한다. 마지막으로 세 번째 디자인 연구에서는 임의의 유전자군의 유전자 발현 패턴을 주요 암 유형에 따라 시각화하고 분석할 수 있는 시스템인 GeneVis를 설계하였다. 암 유형에 따른 유전자 발현 패턴의 분석과 비교는 암 연구자들이 정밀 의학에서 생체 지표(Biomarker)를 발견하기 위해 빈번히 수행하는 작업이다. 우리는 종양학 전문가 및 유전체학 전문가 총 4인을 대상으로 사례 연구를 진행하였고, 그 결과 GeneVis가 해당 작업을 더 수월하게 수행하는 것과 기존의 데이터에서 새로운 정보를 도출하는 것에 도움이 되었음을 확인하였다. 위의 세 디자인 연구의 결과를 바탕으로, 본 논문은 사용자 분석과 작업 분석을 동반한 시각적 분석 방법론이 의학 연구의 근거 관련 작업의 어려움을 해소하고, 분석 데이터에 대한 보다 나은 이해를 제공하는 것이 가능하다고 결론 내린다.CHAPTER1 Introduction 1 1.1 Background and Motivation 1 1.2 Dissertation Outline 5 CHAPTER2 Related Work 7 2.1 Evidence Mapping: Graphical Representation for a Scientific Evidence Landscape 7 2.2 Scientific Literature Visualizations and Bibliography Visualizations 9 2.3 Visual Anlytics Systems for Genomics Data sets and Research Tasks 10 CHAPTER3 PLOEM: An Interactive Visualization Tool for Effective Evidence Mapping with Biomedical literature 12 3.1 Introduction 12 3.2 Visual Representations and Interactions of PLOEM 14 3.2.1 Overview of the PICO Criteria 14 3.2.2 Trend Visualization with the Timeline view 17 3.2.3 Representing the PICO Co-occurrence with the Relation view 20 3.2.4 Study detail view 22 3.3 Usage Scenarios: Visualizing Various Study Sizes with PLOEM 23 3.4 Conclusion 24 CHAPTER4 EEEvis: Efficacy improvement in searching MEDLINE database using a novel PubMed visual analytic system 26 4.1 Introduction 26 4.1.1 Motivation 26 4.1.2 Preliminary Survey: A Questionnaire on conventional literature search methods 28 4.1.3 Design Requirements for Biomedical Literature Search Systems 36 4.2 System and Interface Implementation of EEEVis 37 4.2.1 System Overview 37 4.2.2 Bibliography Filters 40 4.2.3 Timeline View 41 4.2.4 Co-authorship Network View 43 4.2.5 Article List and Detail View 44 4.3 User Study 46 4.3.1 Participants 46 4.3.2 Procedures 48 4.3.3 Results and Observations 50 4.4 Discussion 54 4.4.1 Design Implications 56 4.4.2 Limitations and Future Work 57 4.5 Conclusions 59 CHAPTER5 GeneVis: A Visual Analytics Systemfor Gene Signature Analysis in Cancers 68 5.1 Motivation 68 5.2 System and Interface Implementation 69 5.2.1 System Overview 69 5.2.2 Gene Expression Detail View 71 5.2.3 Gene Vector Projection View 72 5.2.4 Gene x Cancer Type Heatmap view 74 5.2.5 User Interaction in Multiple Coordinated Views 76 5.3 Case Studies 76 5.3.1 Participants 76 5.3.2 Task and Procedures 76 5.3.3 Case1: Identifying SimilarGeneSignatures with TGFB1in Hallmark Gene Sets 80 5.3.4 Case2: Identifying Cluster Patterns in the HRD data set 81 5.3.5 Results 82 5.4 Summary 85 CHAPTER6 Conclusion and future work 86 6.1 Conclusion 86 6.2 Future Work 87 Abstract (Korean) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102박

Personalised interactive music systems for physical activity and exercise: a systematic review and meta-analysis

The use of Personalised Interactive Music Systems (PIMS) may provide benefits in promoting physical activity levels. This systematic review and meta-analysis was conducted to assess the overall impact of PIMS in physical activity and exercise domains. Separate random effects meta-analyses were conducted for outcomes in physical activity levels, physical exertion, rate of perceived exertion(RPE), and affect. In total, 18 studies were identified. Of these, six studies (with17 total intervention arms) reported data on at least one outcome of interest, from which an effect size could be calculated. PIMS were significantly associated with beneficial changes in physical activity levels (g = 0.49, CI [0.07, 0.91], p = 0.02,k = 4, n = 76) and affect (g = 1.68, CI [0.15, 3.20], p = 0.03, k = 4, n = 122).However, no significant benefit of PIMS use was found for RPE (g = 0.72, CI [-0.14, 1.59], p = 0.10, k = 3, n = 77) or physical exertion (g = 0.79, CI [-0.64,2.10], p = 0.28, k = 5, n = 142). Overall, results support the preliminary use of PIMS across a variety of physical activities to promote physical activity levels and positive affect

Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments:A network meta-analysis

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the benefits and harms of each cholinesterase inhibitor in the treatment of adults with VCI. To compare cholinesterase inhibitors for efficacy and safety in people with VCI