Biostatistics Commons^™

Statistical Handling Of Medical Data - An Ethical Perspective, Ajay Kumar Bansal Dr

COBRA Preprint Series

Medical Science is a delicate subject and the clinical data generated from the medical trials must be reliable and of good quality. Not only the quality of generated data is important, but the management is also crucial and is to be handled very carefully. In this paper, the ethical aspect of statistical handling of such data is discussed.

Every profession has some set of norms to follow to achieve its objectives. These norms are called professional ethics which shows the essence of human behaviour. Same way, the field of medical research is expected to follow ethical norms, to obtain reliable …

Semi-Parametric Estimation And Inference For The Mean Outcome Of The Single Time-Point Intervention In A Causally Connected Population, Oleg Sofrygin, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We study the framework for semi-parametric estimation and statistical inference for the sample average treatment-specific mean effects in observational settings where data are collected on a single network of connected units (e.g., in the presence of interference or spillover). Despite recent advances, many of the current statistical methods rely on estimation techniques that assume a particular parametric model for the outcome, even though some of the most important statistical assumptions required by these models are most likely violated in the observational network settings, often resulting in invalid and anti-conservative statistical inference. In this manuscript, we rely on the recent methodological …

Statistical Estimation Of White Matter Microstructure From Conventional Mri, Leah Suttner, Amanda Mejia, Blake Dewey, Pascal Sati, Daniel S. Reich, Russell T. Shinohara

UPenn Biostatistics Working Papers

Diffusion tensor imaging (DTI) has become the predominant modality for studying white matter integrity in multiple sclerosis (MS) and other neurological disorders. Unfortunately, the use of DTI-based biomarkers in large multi-center studies is hindered by systematic biases that confound the study of disease-related changes. Furthermore, the site-to-site variability in multi-center studies is significantly higher for DTI than that for conventional MRI-based markers. In our study, we apply the Quantitative MR Estimation Employing Normalization (QuEEN) model to estimate the four DTI measures: MD, FA, RD, and AD. QuEEN uses a voxel-wise generalized additive regression model to relate the normalized intensities of …

Correction Of Verication Bias Using Log-Linear Models For A Single Binaryscale Diagnostic Tests, Haresh Rochani, Hani M. Samawi, Robert L. Vogel, Jingjing Yin

Biostatistics Faculty Publications

In diagnostic medicine, the test that determines the true disease status without an error is referred to as the gold standard. Even when a gold standard exists, it is extremely difficult to verify each patient due to the issues of costeffectiveness and invasive nature of the procedures. In practice some of the patients with test results are not selected for verification of the disease status which results in verification bias for diagnostic tests. The ability of the diagnostic test to correctly identify the patients with and without the disease can be evaluated by measures such as sensitivity, specificity and predictive …

A Generally Efficient Targeted Minimum Loss Based Estimator, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

Suppose we observe n independent and identically distributed observations of a finite dimensional bounded random variable. This article is concerned with the construction of an efficient targeted minimum loss-based estimator (TMLE) of a pathwise differentiable target parameter based on a realistic statistical model.

The canonical gradient of the target parameter at a particular data distribution will depend on the data distribution through an infinite dimensional nuisance parameter which can be defined as the minimizer of the expectation of a loss function (e.g., log-likelihood loss). For many models and target parameters the nuisance parameter can be split up in two components, …

Corn-Soybean And Alternative Cropping Systems Effects On No 3 -N Leaching Losses In Subsurface Drainage Water, Rameshwar S. Kanwar, Richard M. Cruse, Mohammadreza Ghaffarzadeh, Allah Bakhsh, Douglas Karlen, Theodore B. Bailey

Douglas L Karlen

Alternative cropping systems can improve resource use efficiency, increase corn grain yield, and help in reducing negative impacts on the environment. A 6-yr (1993 to 1998) field study was conducted at the Iowa State University’s Northeastern Research Center near Nashua, Iowa, to evaluate the effects of non-traditional cropping systems [strip inter cropping (STR)-corn (Zea mays L.)/soybean (Glycine max L.)/oats (Avina sativa L.)]; alfalfa rotation (ROT)-3-yr (1993 to 1995) alfalfa (Medicago sativa L.) followed by corn in 1996, soybean in 1997, and oats in 1998), and traditional cropping system (corn after soybean (CS) and soybean after corn (SC) on the flow …

Cropping System Effects On No3-N Loss With Subsurface Drainage Water, Allah Bakhsh, Rameshwar S. Kanwar, Theodore B. Bailey, Cynthia A. Cambardella, Douglas Karlen, Thomas S. Colvin

Douglas L Karlen

An appropriate combination of tillage and nitrogen management practices will be necessary to develop sustainable farming practices. A six–year (1993–1998) field study was conducted on subsurface–drained Clyde–Kenyon–Floyd soils to quantify the impact of two tillage systems (chisel plow vs. no tillage) and two N fertilizer management practices (preplant single application vs. late–spring soil test based application) on nitrate–nitrogen (NO3–N) leaching loss with subsurface drain discharge from corn (Zea mays L.) soybean (Glycine max L.) rotation plots. Preplant injected urea ammonium nitrate solution (UAN) fertilizer was applied at the rate of 110 kg ha–1 to chisel plow and no–till corn plots, …

Effects Of Cost Sharing On Seeking Care For Serious And Minor Symptoms. Results Of A Randomized Controlled Trial, Martin Shapiro, John Ware, Cathy Sherbourne

Martin Shapiro

To estimate the effect of cost sharing on seeking care for serious and minor symptoms, we analyzed data for 3539 persons aged 17 to 61 from the Rand Health Insurance Experiment. Participants were randomly assigned to a free-care group or to insurance plans requiring them to pay part of the costs (cost-sharing group). Annual surveys were administered to determine if participants had serious and minor symptoms during the preceding month and whether they saw a physician. Serious symptoms were judged by a panel of physicians to warrant care in most instances; minor symptoms were judged neither to be severe nor …

Estimated Probability Of Becoming Alcohol Dependent: Extending A Multiparametric Approach, Olga A. Vsevolozhskaya, James C. Anthony

Biostatistics Presentations

Background: United States (US) epidemiological studies suggest that for every 5-8 who start drinking alcoholic beverages, at least one drinker will develop an alcohol dependence (AD) syndrome within the first 10 years after onset of drinking (Lopez-Quintero et al., 2011; Wagner & Anthony, 2002). Recently, we described a multiparametric functional analysis approach for new research to estimate these transition probabilities with a one-dimensional function (1D; Vsevolozhskaya & Anthony, 2015). Here, we demonstrate extension of this analysis to two-dimensional (2D) functions that combine information about number of recent drinking days and number of drinks on the typical drinking day.

Methods: Data …

Inequality In Treatment Benefits: Can We Determine If A New Treatment Benefits The Many Or The Few?, Emily Huang, Ethan Fang, Daniel Hanley, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

The primary analysis in many randomized controlled trials focuses on the average treatment effect and does not address whether treatment benefits are widespread or limited to a select few. This problem affects many disease areas, since it stems from how randomized trials, often the gold standard for evaluating treatments, are designed and analyzed. Our goal is to learn about the fraction who benefit from a treatment, based on randomized trial data. We consider the case where the outcome is ordinal, with binary outcomes as a special case. In general, the fraction who benefit is a non-identifiable parameter, and the best …

Factors Impacting Transgender Patients’ Discomfort With Their Family Physicians: A Respondent-Driven Sampling Survey, Greta R. Bauer, Xuchen Zong, Ayden I. Scheim, Rebecca Hammond, Amardeep Thind

Epidemiology and Biostatistics Publications

BACKGROUND: Representing approximately 0.5% of the population, transgender (trans) persons in Canada depend on family physicians for both general and transition-related care. However, physicians receive little to no training on this patient population, and trans patients are often profoundly uncomfortable and may avoid health care. This study examined factors associated with patient discomfort discussing trans health issues with a family physician in Ontario, Canada.

METHODS: 433 trans people age 16 and over were surveyed using respondent-driven sampling for the Trans PULSE Project; 356 had a family physician. Weighted logistic regression models were fit to produce prevalence risk ratios (PRRs) via …

Niche-Based Modeling Of Japanese Stiltgrass (Microstegium Vimineum) Using Presence-Only Information, Nathan Bush

Masters Theses

The Connecticut River watershed is experiencing a rapid invasion of aggressive non-native plant species, which threaten watershed function and structure. Volunteer-based monitoring programs such as the University of Massachusetts’ OutSmart Invasives Species Project, Early Detection Distribution Mapping System (EDDMapS) and the Invasive Plant Atlas of New England (IPANE) have gathered valuable invasive plant data. These programs provide a unique opportunity for researchers to model invasive plant species utilizing citizen-sourced data. This study took advantage of these large data sources to model invasive plant distribution and to determine environmental and biophysical predictors that are most influential in dispersion, and to identify …

Monitoring For Adverse Events Post Marketing Approval Of Drugs, Karl E. Peace, Macaulay Okwuokenye

Biostatistics Faculty Publications

This brief communication provides information to those developing monitoring plans for serious adverse events (SAE’s) following regulatory approval of a new drug. In addition, we (1) illustrate how many patients would need to be treated in order to have high confidence of seeing at least 1 pre-specified SAE, (2) show that absence of proof of a SAE is not proof of absence of that SAE, and (3) identify statistical methodology that could be used for formal statistical monitoring of SAE’s.

Meta-Analysis Of Genome-Wide Association Studies With Correlated Individuals: Application To The Hispanic Community Health Study/Study Of Latinos (Hchs/Sol), Tamar Sofer, John R. Shaffer, Misa Graff, Qibin Qi, Adrienne M. Stilp, Stephanie M. Gogarten, Kari E. North, Carmen R. Isasi, Cathy C. Laurie, Adam A. Szpiro

UW Biostatistics Working Paper Series

Investigators often meta-analyze multiple genome-wide association studies (GWASs) to increase the power to detect associations of single nucleotide polymorphisms (SNPs) with a trait. Meta-analysis is also performed within a single cohort that is stratified by, e.g., sex or ancestry group. Having correlated individuals among the strata may complicate meta-analyses, limit power, and inflate Type 1 error. For example, in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), sources of correlation include genetic relatedness, shared household, and shared community. We propose a novel mixed-effect model for meta-analysis, “MetaCor", which accounts for correlation between stratum-specific effect estimates. Simulations show that MetaCor controls …

Physical Activity Classification With Conditional Random Fields, Evan L. Ray

Doctoral Dissertations

In this thesis we develop methods for classifying physical activity using accelerometer recordings. We cast this as a problem of classification in time series with moderate to high dimensional observations at each time point. Specifically, we observe a vector of summary statistics of the accelerometer signal at each point in time, and we wish to use these observations to estimate the type and intensity of physical activity the individual engaged in as it changes over time. Our methods are based on Conditional Random Fields, which allow us to capture temporal dependence in an individual’s physical activity type without requiring us …

Nested Partially-Latent, Class Models For Dependent Binary Data, Estimating Disease Etiology, Zhenke Wu, Maria Deloria-Knoll, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

The Pneumonia Etiology Research for Child Health (PERCH) study seeks to use modern measurement technology to infer the causes of pneumonia for which gold-standard evidence is unavailable. The paper describes a latent variable model designed to infer from case-control data the etiology distribution for the population of cases, and for an individual case given his or her measurements. We assume each observation is drawn from a mixture model for which each component represents one cause or disease class. The model addresses a major limitation of the traditional latent class approach by taking account of residual dependence among multivariate binary outcome …

Abcc9/Sur2 In The Brain: Implications For Hippocampal Sclerosis Of Aging And A Potential Therapeutic Target, Peter T. Nelson, Gregory A. Jicha, Wang-Xia Wang, Eseosa T. Ighodaro, Sergey C. Artiushin, Colin G. Nichols, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“K _ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K _ATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is …

Identification And Survival Outcomes Of A Cohort Of Patients With Cancer Of Unknown Primary In Ontario, Canada., Chong S Kim, Malek B Hannouf, Sisira Sarma, George B Rodrigues, Peter K Rogan, Salaheddin M Mahmud, Eric Winquist, Muriel Brackstone, Gregory S Zaric

Epidemiology and Biostatistics Publications

BACKGROUND: Cancer of unknown primary origin (CUP) is defined by the presence of pathologically identified metastatic disease without clinical or radiological evidence of a primary tumour. Our objective was to identify incident cases of CUP in Ontario, Canada, and determine the influence of histology and sites of metastases on overall survival (OS).

MATERIAL AND METHODS: We used the Ontario Cancer Registry (OCR) and the Same-Day Surgery and Discharge Abstract Database (SDS/DAD) to identify patients diagnosed with CUP in Ontario between 1 January 2000, and 31 December 2005. Patient diagnostic information, including histology and survival data, was obtained from the OCR. …

Flexible Penalized Regression For Functional Data...And Other Complex Data Objects, Philip T. Reiss

Philip T. Reiss

No abstract provided.

Removing Inter-Subject Technical Variability In Magnetic Resonance Imaging Studies, Jean-Philippe Fortin, Elizabeth M. Sweeney, John Muschelli, Ciprian M. Crainiceanu, Russell T. Shinohara, Alzheimer’S Disease Neuroimaging Initiative

UPenn Biostatistics Working Papers

Magnetic resonance imaging (MRI) intensities are acquired in arbitrary units, making scans non-comparable across sites and between subjects. Intensity normalization is a first step for the improvement of comparability of the images across subjects. However, we show that unwanted inter-scan variability associated with imaging site, scanner effect and other technical artifacts is still present after standard intensity normalization in large multi-site neuroimaging studies. We propose RAVEL (Removal of Artificial Voxel Effect by Linear regression), a tool to remove residual technical variability after intensity normalization. As proposed by SVA and RUV [Leek and Storey, 2007, …

Integrated Bioinformatics, Environmental Epidemiologic And Genomic Approaches To Identify Environmental And Molecular Links Between Endometriosis And Breast Cancer, Deodutta Roy, Marisa L. Morgan, Changwon Yoo, Alok Deoraj, Sandhya Roy, Vijay Kumar Yadav, Mohannad Garoub, Hamza Assaggaf, Mayur Doke

Department of Biostatistics Faculty Publications

We present a combined environmental epidemiologic, genomic, and bioinformatics approach to identify: exposure of environmental chemicals with estrogenic activity; epidemiologic association between endocrine disrupting chemical (EDC) and health effects, such as, breast cancer or endometriosis; and gene-EDC interactions and disease associations. Human exposure measurement and modeling confirmed estrogenic activity of three selected class of environmental chemicals, polychlorinated biphenyls (PCBs), bisphenols (BPs), and phthalates. Meta-analysis showed that PCBs exposure, not Bisphenol A (BPA) and phthalates, increased the summary odds ratio for breast cancer and endometriosis. Bioinformatics analysis of gene-EDC interactions and disease associations identified several hundred genes that were altered by …

Type 2 Diabetes And Its Correlates Among Adults In Bangladesh: A Population Based Stud, Muhammad Abdul Baker Chowdhury, Md Jamal Uddin, Hafiz M.R. Khan, Md Rabiul Haque

Department of Biostatistics Faculty Publications

Type 2 diabetes is one of the most prevalent non-communicable diseases in Bangladesh. However, the correlates of type 2 diabetes among adults in Bangladesh remain unknown. We aimed to investigate the correlates of type 2 diabetes among the adults in Bangladesh.

Methods : We conducted a cross-sectional study using data from the nationally representative 2011 Bangladesh Demographic and Health Survey. A random sample of 7,543 (3,823 women and 3,720 men) adults of age 35 years and older from both urban and rural areas, who participated in the survey was included. Diabetes was defined as having a fasting plasma blood glucose …

An Omnibus Nonparametric Test Of Equality In Distribution For Unknown Functions, Alexander Luedtke, Marco Carone, Mark Van Der Laan

Alex Luedtke

We present a novel family of nonparametric omnibus tests of the hypothesis that two unknown but estimable functions are equal in distribution when applied to the observed data structure. We developed these tests, which represent a generalization of the maximum mean discrepancy tests described in Gretton et al. [2006], using recent developments from the higher-order pathwise differentiability literature. Despite their complex derivation, the associated test statistics can be expressed rather simply as U-statistics. We study the asymptotic behavior of the proposed tests under the null hypothesis and under both fixed and local alternatives. We provide examples to which our tests …

Computerizing Efficient Estimation Of A Pathwise Differentiable Target Parameter, Mark J. Van Der Laan, Marco Carone, Alexander R. Luedtke

Alex Luedtke

Frangakis et al. (2015) proposed a numerical method for computing the efficient influence function of a parameter in a nonparametric model at a specified distribution and observation (provided such an influence function exists). Their approach is based on the assumption that the efficient influence function is given by the directional derivative of the target parameter mapping in the direction of a perturbation of the data distribution defined as the convex line from the data distribution to a pointmass at the observation. In our discussion paper Luedtke et al. (2015) we propose a regularization of this procedure and establish the validity …

Validation Of A New Predictive Risk Model: Measuring The Impact Of The Major Modifiable Risks Of Death For Patients And Populations, Stephen S. Lim, Emily Carnahan, Eugene C. Nelson, Catherine W. Gillespie, Ali H. Mokdad, Christopher J. L. Murray, Elliott S. Fisher

Dartmouth Scholarship

Background: Modifiable risks account for a large fraction of disease and death, but clinicians and patients lack tools to identify high risk populations or compare the possible benefit of different interventions.

Methods: We used data on the distribution of exposure to 12 major behavioral and biometric risk factors inthe US population, mortality rates by cause, and estimates of the proportional hazards of risk factor exposure from published systematic reviews to develop a risk prediction model that estimates an adult's 10 year mortality risk compared to a population with optimum risk factors. We compared predicted risk to observed mortality in 8,241 …

Functional Linear Models Extensions Uncover Pleiotropic Effects Of Chronic Pain Phenotypes, Dmitri V. Zaykin, L. Qing, G. D. Slade, R. Dubner, R. B. Fillingim, J. D. Greenspan, R. Ohrbach, W. Maixner, L. B. Diatchenko, Olga A. Vsevolozhskaya

Biostatistics Presentations

Growing scientific evidence suggests that intricate interactions of genetic risk factors with environmental exposures play a major role in the development of chronic pain conditions. In studies of relative contribution of an individual’s genetic composition to the perception of pain, the general characteristics of pain sensitivity are typically measured by a wide range of different, yet possibly etiologically related pain phenotypes. Testing each of these pain-perception traits individually is subject to problems of multiple testing and low statistical power. Furthermore, pain-related traits may share common etiology and comprise binary, categorical, and quantitative measurements. In the current study, we propose a …

Patient-Specific Variations In Biomarkers Across Gingivitis And Periodontitis, Radhakrishnan Nagarajan, Craig S. Miller, Dolph Dawson, Mohanad Al-Sabbagh, J. L. Ebersole

Biostatistics Faculty Publications

This study investigates the use of saliva, as an emerging diagnostic fluid in conjunction with classification techniques to discern biological heterogeneity in clinically labelled gingivitis and periodontitis subjects (80 subjects; 40/group) A battery of classification techniques were investigated as traditional single classifier systems as well as within a novel selective voting ensemble classification approach (SVA) framework. Unlike traditional single classifiers, SVA is shown to reveal patient-specific variations within disease groups, which may be important for identifying proclivity to disease progression or disease stability. Salivary expression profiles of IL-1ß, IL-6, MMP-8, and MIP-1α from 80 patients were analyzed using four classification …

Addressing Confounding In Predictive Models With An Application To Neuroimaging, Kristin A. Linn, Bilwaj Gaonkar, Jimit Doshi, Christos Davatzikos, Russell T. Shinohara

UPenn Biostatistics Working Papers

Understanding structural changes in the brain that are caused by a particular disease is a major goal of neuroimaging research. Multivariate pattern analysis (MVPA) comprises a collection of tools that can be used to understand complex disease effects across the brain. We discuss several important issues that must be considered when analyzing data from neuroimaging studies using MVPA. In particular, we focus on the consequences of confounding by non-imaging variables such as age and sex on the results of MVPA. After reviewing current practice to address confounding in neuroimaging studies, we propose an alternative approach based on inverse probability weighting. …

Control-Group Feature Normalization For Multivariate Pattern Analysis Using The Support Vector Machine, Kristin A. Linn, Bilwaj Gaonkar, Jimit Doshi, Christos Davatzikos, Russell T. Shinohara

UPenn Biostatistics Working Papers

Normalization of feature vector values is a common practice in machine learning. Generally, each feature value is standardized to the unit hypercube or by normalizing to zero mean and unit variance. Classification decisions based on support vector machines (SVMs) or by other methods are sensitive to the specific normalization used on the features. In the context of multivariate pattern analysis using neuroimaging data, standardization effectively up- and down-weights features based on their individual variability. Since the standard approach uses the entire data set to guide the normalization it utilizes the total variability of these features. This total variation is inevitably …

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

COBRA Preprint Series

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 …