Biostatistics Commons^™

Bayesian Approach On Short Time-Course Data Of Protein Phosphorylation, Casual Inference For Ordinal Outcome And Causal Analysis Of Dietary And Physical Activity In T2dm Using Nhanes Data., You Wu

Electronic Theses and Dissertations

This dissertation contains three different projects in proteomics and causal inferences. In the first project, I apply a Bayesian hierarchical model to assess the stability of phosphorylated proteins under short-time cold ischemia. This study provides inference on the stability of these phosphorylated proteins, which is valuable when using these proteins as biomarkers for a disease. in the second project, I perform a comparative study of different confounding-adjusted to estimate the treatment effect when the outcome variable is ordinal using observational data. The adjusted U-statistics method is compared with other methods such as ordinal logistic regression, propensity score based stratification and …

Impact Of Home Visit Capacity On Genetic Association Studies Of Late-Onset Alzheimer's Disease, David W. Fardo, Laura E. Gibbons, Shubhabrata Mukherjee, M. Maria Glymour, Wayne Mccormick, Susan M. Mccurry, James D. Bowen, Eric B. Larson, Paul K. Crane

Biostatistics Faculty Publications

INTRODUCTION—Findings for genetic correlates of late-onset Alzheimer's disease (LOAD) in studies that rely solely on clinic visits may differ from those with capacity to follow participants unable to attend clinic visits.

METHODS—We evaluated previously identified LOAD-risk single nucleotide variants in the prospective Adult Changes in Thought study, comparing hazard ratios (HRs) estimated using the full data set of both in-home and clinic visits (n = 1697) to HRs estimated using only data that were obtained from clinic visits (n = 1308). Models were adjusted for age, sex, principal components to account for ancestry, and additional health indicators.

RESULTS …

Novel Bayesian Adaptive Clinical Trial Designs In Early Phases, Haitao Pan

Dissertations and Theses (Open Access)

Early phase, or phase I and phase II, trials are the first step in testing new medicines that have been developed in the lab. The main goal of phase I clinical trials is to establish the recommended dose of new drugs for phase II trials. For the cytotoxic drugs, the goal is to find maximum tolerated dose (MTD). The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Therefore, dose escalation methods, especially Bayesian designs, are recommended to be used in phase I …

A Tail-Based Test For Differential Expression Analysis And Pathway Analysis In Rna-Sequencing Data, Jiong Chen

Dissertations and Theses (Open Access)

RNA sequencing data have been abundantly generated in biomedical research for biomarker discovery and pathway analysis. Such data at the exon-level are usually heavily tailed and correlated. Conventional statistical tests based on the mean or median difference for differential expression likely suffer from low power when the between-group difference occurs mostly in the upper or lower tail of the distribution of gene expression. We propose a tail-based test to make comparisons between groups in terms of a specific distribution area rather than a single location. The proposed test, which is derived from quantile regression, adjusts for covariates and accounts for …

Application Of Support Vector Machine Modeling And Graph Theory Metrics For Disease Classification, Jessica M. Rudd

Published and Grey Literature from PhD Candidates

Disease classification is a crucial element of biomedical research. Recent studies have demonstrated that machine learning techniques, such as Support Vector Machine (SVM) modeling, produce similar or improved predictive capabilities in comparison to the traditional method of Logistic Regression. In addition, it has been found that social network metrics can provide useful predictive information for disease modeling. In this study, we combine simulated social network metrics with SVM to predict diabetes in a sample of data from the Behavioral Risk Factor Surveillance System. In this dataset, Logistic Regression outperformed SVM with ROC index of 81.8 and 81.7 for models with …

Combining Biomarkers By Maximizing The True Positive Rate For A Fixed False Positive Rate, Allison Meisner, Marco Carone, Margaret Pepe, Kathleen F. Kerr

UW Biostatistics Working Paper Series

Biomarkers abound in many areas of clinical research, and often investigators are interested in combining them for diagnosis, prognosis and screening. In many applications, the true positive rate for a biomarker combination at a prespecified, clinically acceptable false positive rate is the most relevant measure of predictive capacity. We propose a distribution-free method for constructing biomarker combinations by maximizing the true positive rate while constraining the false positive rate. Theoretical results demonstrate good operating characteristics for the resulting combination. In simulations, the biomarker combination provided by our method demonstrated improved operating characteristics in a variety of scenarios when compared with …

Developing Biomarker Combinations In Multicenter Studies Via Direct Maximization And Penalization, Allison Meisner, Chirag R. Parikh, Kathleen F. Kerr

UW Biostatistics Working Paper Series

When biomarker studies involve patients at multiple centers and the goal is to develop biomarker combinations for diagnosis, prognosis, or screening, we consider evaluating the predictive capacity of a given combination with the center-adjusted AUC (aAUC), a summary of conditional performance. Rather than using a general method to construct the biomarker combination, such as logistic regression, we propose estimating the combination by directly maximizing the aAUC. Furthermore, it may be desirable to have a biomarker combination with similar predictive capacity across centers. To that end, we allow for penalization of the variability in center-specific performance. We demonstrate good asymptotic properties …

Testing The Independence Hypothesis Of Accepted Mutations For Pairs Of Adjacent Amino Acids In Protein Sequences, Jyotsna Ramanan, Peter Revesz

School of Computing: Faculty Publications

Evolutionary studies usually assume that the genetic mutations are independent of each other. However, that does not imply that the observed mutations are independent of each other because it is possible that when a nucleotide is mutated, then it may be biologically beneficial if an adjacent nucleotide mutates too. With a number of decoded genes currently available in various genome libraries and online databases, it is now possible to have a large-scale computer-based study to test whether the independence assumption holds for pairs of adjacent amino acids. Hence the independence question also arises for pairs of adjacent amino acids within …

Visualizing Lab And Phenotype Associations Using Phewas And Electronic Health Records, Brenda Emerson, Miriam Goldman, Sahiti Kolli

Honors Projects

As the digitization of patient health records is becoming more common, we are given a great opportunity to analyze these records and hopefully make discoveries about diseases or medicines. Being given large datasets of Electronic Health Records, I and two other students decided to look for novel phenotype associations with mean lab values, look to see whether the presence of a lab had associations with a phenotype, and create an interactive application to visual the associations between labs and phenotypes.

Peripheral Inflammation, Apolipoprotein E4, And Amyloid-Β Interact To Induce Cognitive And Cerebrovascular Dysfunction, Felecia M. Marottoli, Yuriko Katsumata, Kevin P. Koster, Riya Thomas, David W. Fardo, Leon M. Tai

Biostatistics Faculty Publications

Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of …

Burden Of Atopic Dermatitis In The United States: Analysis Of Healthcare Claims Data In The Commercial, Medicare, And Medi-Cal Databases, Sulena Shrestha, Raymond Miao, Li Wang, Jingdong Chao, Huseyin Yuce, Wenhui Wei

Publications and Research

Comparative data on the burden of atopic dermatitis (AD) in adults relative to the general population are limited. We performed a large-scale evaluation of the burden of disease among US adults with AD relative to matched non-AD controls, encompassing comorbidities, healthcare resource utilization (HCRU), and costs, using healthcare claims data. The impact of AD disease severity on these outcomes was also evaluated.

Biomarker Combinations For Diagnosis And Prognosis In Multicenter Studies: Principles And Methods, Allison Meisner, Chirag R. Parikh, Kathleen F. Kerr

UW Biostatistics Working Paper Series

Many investigators are interested in combining biomarkers to predict an outcome of interest or detect underlying disease. This endeavor is complicated by the fact that many biomarker studies involve data from multiple centers. Depending upon the relationship between center, the biomarkers, and the target of prediction, care must be taken when constructing and evaluating combinations of biomarkers. We introduce a taxonomy to describe the role of center and consider how a biomarker combination should be constructed and evaluated. We show that ignoring center, which is frequently done by clinical researchers, is often not appropriate. The limited statistical literature proposes using …

Mixture Models For Undiagnosed Prevalent Disease And Interval-Censored Incident Disease: Applications To A Cohort Assembled From Electronic Health Records., Li C Cheung, Qing Pan, Noorie Hyun, Mark Schiffman, Barbara Fetterman, Philip E Castle, Thomas Lorey, Hormuzd A Katki

Epidemiology Faculty Publications

For cost-effectiveness and efficiency, many large-scale general-purpose cohort studies are being assembled within large health-care providers who use electronic health records. Two key features of such data are that incident disease is interval-censored between irregular visits and there can be pre-existing (prevalent) disease. Because prevalent disease is not always immediately diagnosed, some disease diagnosed at later visits are actually undiagnosed prevalent disease. We consider prevalent disease as a point mass at time zero for clinical applications where there is no interest in time of prevalent disease onset. We demonstrate that the naive Kaplan-Meier cumulative risk estimator underestimates risks at early …

Safety Of Induced Sputum Collection In Children Hospitalized With Severe Or Very Severe Pneumonia., Andrea N Deluca, Laura L Hammitt, Julia Kim, Melissa M Higdon, Henry C Baggett, Daniel E Park, +Several Additional Authors

Epidemiology Faculty Publications

Background.: Induced sputum (IS) may provide diagnostic information about the etiology of pneumonia. The safety of this procedure across a heterogeneous population with severe pneumonia in low- and middle-income countries has not been described.

Methods.: IS specimens were obtained as part a 7-country study of the etiology of severe and very severe pneumonia in hospitalized childrenbefore, during, and after the procedure to record oxygen requirement, oxygen saturation, respiratory rate, consciousness level, and other evidence of clinical deterioration. Criteria for IS contraindications were predefined and serious adverse events (SAEs) were reported to ethics committees and a central safety monitor.

Results.: A …

Data Management And Data Quality In Perch, A Large International Case-Control Study Of Severe Childhood Pneumonia., Nora L Watson, Christine Prosperi, Amanda J Driscoll, Melissa M Higdon, Daniel E Park, Megan Sanza, Andrea N Deluca, Juliet O Awori, Doli Goswami, Emily Hammond, Lokman Hossain, Catherine Johnson, Alice Kamau, Locadiah Kuwanda, David P Moore, Omid Neyzari, Uma Onwuchekwa, David Parker, Patranuch Sapchookul

Epidemiology Faculty Publications

The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed …

Colonization Density Of The Upper Respiratory Tract As A Predictor Of Pneumonia-Haemophilus Influenzae, Moraxella Catarrhalis, Staphylococcus Aureus, And Pneumocystis Jirovecii., Daniel E Park, Henry C Baggett, Stephen R C Howie, Qiyuan Shi, Nora L Watson, W Abdullah Brooks, Perch Study Group

Epidemiology Faculty Publications

Background.

There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii. Methods.

In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or …

Microscopic Analysis And Quality Assessment Of Induced Sputum From Children With Pneumonia In The Perch Study., David R Murdoch, Susan C Morpeth, Laura L Hammitt, Amanda J Driscoll, Daniel E Park, +Several Additional Authors

Epidemiology Faculty Publications

Background.

It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. Methods.

We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1–59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative …

Is Higher Viral Load In The Upper Respiratory Tract Associated With Severe Pneumonia? Findings From The Perch Study., Daniel R Feikin, Wei Fu, Daniel E Park, Qiyuan Shi, Melissa M Higdon, Henry C Baggett, +Several Additional Authors

Epidemiology Faculty Publications

Background.

The etiologic inference of identifying a pathogen in the upper respiratory tract (URT) of children with pneumonia is unclear. To determine if viral load could provide evidence of causality of pneumonia, we compared viral load in the URT of children with World Health Organization–defined severe and very severe pneumonia and age-matched community controls.

Methods.

In the 9 developing country sites, nasopharyngeal/oropharyngeal swabs from children with and without pneumonia were tested using quantitative real-time polymerase chain reaction for 17 viruses. The association of viral load with case status was evaluated using logistic regression. Receiver operating characteristic (ROC) curves were constructed …

Association Of C-Reactive Protein With Bacterial And Respiratory Syncytial Virus-Associated Pneumonia Among Children Aged <5 Years In The Perch Study., Melissa M Higdon, Tham Le, Katherine L O'Brien, David R Murdoch, Christine Prosperi, Henry C Baggett, Daniel E Park, +Several Additional Authors

Epidemiology Faculty Publications

Background.

Lack of a gold standard for identifying bacterial and viral etiologies of pneumonia has limited evaluation of C-reactive protein (CRP) for identifying bacterial pneumonia. We evaluated the sensitivity and specificity of CRP for identifying bacterial vs respiratory syncytial virus (RSV) pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) multicenter case-control study. Methods.

We measured serum CRP levels in cases with World Health Organization–defined severe or very severe pneumonia and a subset of community controls. We evaluated the sensitivity and specificity of elevated CRP for “confirmed” bacterial pneumonia (positive blood culture or positive lung aspirate or pleural fluid …

Standardization Of Clinical Assessment And Sample Collection Across All Perch Study Sites., Jane Crawley, Christine Prosperi, Henry C Baggett, W Abdullah Brooks, Maria Deloria Knoll, Daniel E Park, +Several Additional Authors

Epidemiology Faculty Publications

Background.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study.

Methods.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency …