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Combining Biomarkers By Maximizing The True Positive Rate For A Fixed False Positive Rate, Allison Meisner, Marco Carone, Margaret Pepe, Kathleen F. Kerr 2017 University of Washington, Seattle

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 2017 University of Washington, Seattle

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 ...


Biomarker Combinations For Diagnosis And Prognosis In Multicenter Studies: Principles And Methods, Allison Meisner, Chirag R. Parikh, Kathleen F. Kerr 2017 University of Washington, Seattle

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 2017 George Washington University

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 and Biostatistics 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 ...


Constructing A Confidence Interval For The Fraction Who Benefit From Treatment, Using Randomized Trial Data, Emily J. Huang, Ethan X. Fang, Daniel F. Hanley, Michael Rosenblum 2017 Johns Hopkins University School of Public Health, Department of Biostatistics

Constructing A Confidence Interval For The Fraction Who Benefit From Treatment, Using Randomized Trial Data, Emily J. Huang, Ethan X. Fang, Daniel F. Hanley, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

The fraction who benefit from treatment is defined as the proportion of patients whose potential outcome under treatment is better than that under control. Statistical inference for this parameter is challenging since it is only partially identifiable, even in our context of a randomized trial. We propose and evaluate a new method for constructing a confidence interval for the fraction who benefit, when the outcome is ordinal-valued (with binary outcomes as a special case). This confidence interval procedure is proved to be pointwise consistent. Our method does not require any assumptions about the joint distribution of the potential outcomes, although ...


Cmer Functions As A Pleiotropic Regulator And Is Required For Optimal Colonization Of Campylobacter Jejuni In Vivo, Baoqing Guo, Ying Wang, Feng Shi, Yi-Wen Barton, Paul J. Plummer, Donald L. Reynolds, Dan Nettleton, Tara Leigh Grinnage-Pulley, Jun Lin, Qijing Zhang 2017 Iowa State University

Cmer Functions As A Pleiotropic Regulator And Is Required For Optimal Colonization Of Campylobacter Jejuni In Vivo, Baoqing Guo, Ying Wang, Feng Shi, Yi-Wen Barton, Paul J. Plummer, Donald L. Reynolds, Dan Nettleton, Tara Leigh Grinnage-Pulley, Jun Lin, Qijing Zhang

Qijing Zhang

CmeR functions as a transcriptional repressor modulating the expression of the multidrug efflux pump CmeABC in Campylobacter jejuni. To determine if CmeR also regulates other genes in C. jejuni, we compared the transcriptome of thecmeR mutant with that of the wild-type strain using a DNA microarray. This comparison identified 28 genes that showed a ≥2-fold change in expression in thecmeR mutant. Independent real-time quantitative reverse transcription-PCR experiments confirmed 27 of the 28 differentially expressed genes. The CmeR-regulated genes encode membrane transporters, proteins involved in C4-dicarboxylate transport and utilization, enzymes for biosynthesis of capsular polysaccharide, and hypothetical proteins with unknown functions ...


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 2017 George Washington University

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 and Biostatistics 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 ...


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 2017 George Washington University

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 and Biostatistics 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 ...


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 2017 George Washington University

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 and Biostatistics 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 ...


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 2017 George Washington University

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 and Biostatistics 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 ...


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 2017 George Washington University

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 and Biostatistics 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 ...


The Diagnostic Utility Of Induced Sputum Microscopy And Culture In Childhood Pneumonia., David R Murdoch, Susan C Morpeth, Laura L Hammitt, Amanda J Driscoll, Nora L Watson, Daniel E Park, +several additional authors 2017 George Washington University

The Diagnostic Utility Of Induced Sputum Microscopy And Culture In Childhood Pneumonia., David R Murdoch, Susan C Morpeth, Laura L Hammitt, Amanda J Driscoll, Nora L Watson, Daniel E Park, +Several Additional Authors

Epidemiology and Biostatistics Faculty Publications

Background.

Sputum microscopy and culture are commonly used for diagnosing the cause of pneumonia in adults but are rarely performed in children due to difficulties in obtaining specimens. Induced sputum is occasionally used to investigate lower respiratory infections in children but has not been widely used in pneumonia etiology studies. Methods.

We evaluated the diagnostic utility of induced sputum microscopy and culture in patients enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study, a large study of community-acquired pneumonia in children aged 1–59 months. Comparisons were made between induced sputum samples from hospitalized children with radiographically confirmed ...


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 2017 George Washington University

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 and Biostatistics 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 ...


Flow Cytometry Is A Promising And Rapid Method For Differentiating Between Freely Suspended Escherichia Coli And E. Coli Attached To Clay Particles, Xiao Liang, Michelle L. Soupir, Shawn M. Rigby, Laura R. Jarboe, Wei Zhang 2017 Iowa State University

Flow Cytometry Is A Promising And Rapid Method For Differentiating Between Freely Suspended Escherichia Coli And E. Coli Attached To Clay Particles, Xiao Liang, Michelle L. Soupir, Shawn M. Rigby, Laura R. Jarboe, Wei Zhang

Laura R. Jarboe

Aim: A standard procedure does not exist to distinguish between attached and unattached micro-organisms. In this study, we compared two methods to quantify between Escherichia coli attached to clay particles and E. coli freely suspended in solution: flow cytometry (attachment assay and viability assay) and settling (or centrifugation followed by settling). Methods and Results: Methods were tested using three environmental strains collected from swine facilities (A, B and C) and one purchased modified pathogenic strain (ATCC 43888); four clay particles: Hectorite, Kaolinite, Ca-Montmorillonite, Montmorillonite K-10; and a range of surface area ratios (particle surface area to E. coli surface area ...


A Simple Method To Estimate The Time-Dependent Roc Curve Under Right Censoring, Liang Li, Bo Hu, Tom Greene 2017 The University of Texas M.D. Anderson Cancer Center

A Simple Method To Estimate The Time-Dependent Roc Curve Under Right Censoring, Liang Li, Bo Hu, Tom Greene

Liang Li

The time-dependent Receiver Operating Characteristic (ROC) curve is often used to study the diagnostic accuracy of a single continuous biomarker, measured at baseline, on the onset of a disease condition when the disease onset may occur at different times during the follow-up and hence may be right censored. Due to censoring, the true disease onset status prior to the pre-specified time horizon may be unknown on some patients, which causes difficulty in calculating the time-dependent sensitivity and specificity. We study a simple method that adjusts for censoring by weighting the censored data by the conditional probability of disease onset prior ...


Optimal, Two Stage, Adaptive Enrichment Designs For Randomized Trials Using Sparse Linear Programming, Michael Rosenblum, Xingyuan Fang, Han Liu 2017 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health

Optimal, Two Stage, Adaptive Enrichment Designs For Randomized Trials Using Sparse Linear Programming, Michael Rosenblum, Xingyuan Fang, Han Liu

Johns Hopkins University, Dept. of Biostatistics Working Papers

Adaptive enrichment designs involve preplanned rules for modifying enrollment criteria based on accruing data in a randomized trial. We focus on designs where the overall population is partitioned into two predefined subpopulations, e.g., based on a biomarker or risk score measured at baseline. The goal is to learn which populations benefit from an experimental treatment. Two critical components of adaptive enrichment designs are the decision rule for modifying enrollment, and the multiple testing procedure. We provide a general method for simultaneously optimizing these components for two stage, adaptive enrichment designs. We minimize the expected sample size under constraints on ...


Impact Of Serum Sp-A And Sp-D Levels On Comparison And Prognosis Of Idiopathic Pulmonary Fibrosis: A Systematic Review And Meta-Analysis., Kai Wang, Qing Ju, Jing Cao, Wenze Tang, Jian Zhang 2017 George Washington University

Impact Of Serum Sp-A And Sp-D Levels On Comparison And Prognosis Of Idiopathic Pulmonary Fibrosis: A Systematic Review And Meta-Analysis., Kai Wang, Qing Ju, Jing Cao, Wenze Tang, Jian Zhang

Epidemiology and Biostatistics Faculty Publications

Background and objective:

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis in general; however, it is heterogeneous to detect relative biomarkers for predicting the disease progression. Serum biomarkers can be conveniently collected to detect and help to differentially diagnose IPF and predict IPF prognosis. This meta-analysis aimed to evaluate the use of serum surfactant proteins A and D (SP-A and SP-D) for differential diagnosis and prognosis of IPF.

Methods:

Relevant articles were searched in PubMed, Embase, and Chinese National Knowledge Infrastructuredatabases and reviewed by 2 independent readers. Standard mean difference (SMD) and 95% confidence interval (CI) were calculated to ...


Disproportionate Subclass Numbers In Tables Of Multiple Classification, George W. Snedecor, Gertrude M. Cox 2017 Iowa State College

Disproportionate Subclass Numbers In Tables Of Multiple Classification, George W. Snedecor, Gertrude M. Cox

Research Bulletin (Iowa Agriculture and Home Economics Experiment Station)

Under the stimulus of some of the newer methods of experimentation there is a decided tendency toward the grouping of classes of data into smaller and more homogeneous sub-classes. The weights of swine, for example, may be simultaneously classified according to the sex as well as the litter of the individual animals. Corn yields may be entered in a three-way table by applying the criteria of variety, treatment and soil type. From the resulting tables of multiple classification can be derived information not only of the main effects, such as sex and litter, but also of the interactions between them ...


Midlife And Late-Life Vascular Risk Factors And White Matter Microstructural Integrity: The Atherosclerosis Risk In Communities Neurocognitive Study., Melinda C Power, Jonathan V Tingle, Robert I Reid, Juebin Huang, A Richey Sharrett, Josef Coresh, Michael Griswold, Kejal Kantarci, Clifford R Jack, David Knopman, Rebecca F Gottesman, Thomas H Mosley 2017 George Washington University

Midlife And Late-Life Vascular Risk Factors And White Matter Microstructural Integrity: The Atherosclerosis Risk In Communities Neurocognitive Study., Melinda C Power, Jonathan V Tingle, Robert I Reid, Juebin Huang, A Richey Sharrett, Josef Coresh, Michael Griswold, Kejal Kantarci, Clifford R Jack, David Knopman, Rebecca F Gottesman, Thomas H Mosley

Epidemiology and Biostatistics Faculty Publications

BACKGROUND: Diffusion tensor imaging measures of white matter (WM) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established. Our study quantifies the association between vascular risk factors in midlife and late life with measures of late-life WM microstructural integrity.

METHODS AND RESULTS: We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3-T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC-NCS). We quantified the association among lipids, glucose, and blood pressure from ...


Cohort Profile: Seek, Test, Treat And Retain United States Criminal Justice Cohort., Redonna Chandler, Michael S Gordon, Bridget Kruszka, Lauren N Strand, Frederick L Altice, Irene Kuo, +several additional authors 2017 George Washington University

Cohort Profile: Seek, Test, Treat And Retain United States Criminal Justice Cohort., Redonna Chandler, Michael S Gordon, Bridget Kruszka, Lauren N Strand, Frederick L Altice, Irene Kuo, +Several Additional Authors

Epidemiology and Biostatistics Faculty Publications

BACKGROUND: The STTR treatment cascade provides a framework for research aimed at improving the delivery of services, care and outcomes of PLWH. The development of effective approaches to increase HIV diagnoses and engage PLWH in subsequent steps of the treatment cascade could lead to earlier and sustained ART treatment resulting in viral suppression. There is an unmet need for research applying the treatment cascade to improve outcomes for those with criminal justice involvement.

METHODS: The Seek, Test, Treat, and Retain (STTR) criminal justice (CJ) cohort combines data from 11 studies across the HIV treatment cascade that focused on persons involved ...


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