Medicine and Health Sciences Commons^™

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 …

Enhanced Precision In The Analysis Of Randomized Trials With Ordinal Outcomes, Iván Díaz, Elizabeth Colantuoni, Michael Rosenblum

Johns Hopkins University, Dept. of Biostatistics Working Papers

We present a general method for estimating the effect of a treatment on an ordinal outcome in randomized trials. The method is robust in that it does not rely on the proportional odds assumption. Our estimator leverages information in prognostic baseline variables, and has all of the following properties: (i) it is consistent; (ii) it is locally efficient; (iii) it is guaranteed to match or improve the precision of the standard, unadjusted estimator. To the best of our knowledge, this is the first estimator of the causal relation between a treatment and an ordinal outcome to satisfy these properties. We …

Partially-Latent Class Models (Plcm) For Case-Control Studies Of Childhood Pneumonia Etiology, Zhenke Wu, Maria Deloria-Knoll, Laura L. Hammitt, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

In population studies on the etiology of disease, one goal is the estimation of the fraction of cases attributable to each of several causes. For example, pneumonia is a clinical diagnosis of lung infection that may be caused by viral, bacterial, fungal, or other pathogens. The study of pneumonia etiology is challenging because directly sampling from the lung to identify the etiologic pathogen is not standard clinical practice in most settings. Instead, measurements from multiple peripheral specimens are made. This paper considers the problem of estimating the population etiology distribution and the individual etiology probabilities. We formulate the scientific …

Estimating Population Treatment Effects From A Survey Sub-Sample, Kara E. Rudolph, Ivan Diaz, Michael Rosenblum, Elizabeth A. Stuart

Johns Hopkins University, Dept. of Biostatistics Working Papers

We consider the problem of estimating an average treatment effect for a target population from a survey sub-sample. Our motivating example is generalizing a treatment effect estimated in a sub-sample of the National Comorbidity Survey Replication Adolescent Supplement to the population of U.S. adolescents. To address this problem, we evaluate easy-to-implement methods that account for both non-random treatment assignment and a non-random two-stage selection mechanism. We compare the performance of a Horvitz-Thompson estimator using inverse probability weighting (IPW) and two double robust estimators in a variety of scenarios. We demonstrate that the two double robust estimators generally outperform IPW in …

Restricted Likelihood Ratio Tests For Functional Effects In The Functional Linear Model, Bruce J. Swihart, Jeff Goldsmith, Ciprian M. Crainiceanu

Johns Hopkins University, Dept. of Biostatistics Working Papers

The goal of our article is to provide a transparent, robust, and computationally feasible statistical approach for testing in the context of scalar-on-function linear regression models. In particular, we are interested in testing for the necessity of functional effects against standard linear models. Our methods are motivated by and applied to a large longitudinal study involving diffusion tensor imaging of intracranial white matter tracts in a susceptible cohort. In the context of this study, we conduct hypothesis tests that are motivated by anatomical knowledge and which support recent findings regarding the relationship between cognitive impairment and white matter demyelination. R-code …

Flexible Distributed Lag Models Using Random Functions With Application To Estimating Mortality Displacement From Heat-Related Deaths, Roger D. Peng

Johns Hopkins University, Dept. of Biostatistics Working Papers

No abstract provided.

Assessing Association For Bivariate Survival Data With Interval Sampling: A Copula Model Approach With Application To Aids Study, Hong Zhu, Mei-Cheng Wang

Johns Hopkins University, Dept. of Biostatistics Working Papers

In disease surveillance systems or registries, bivariate survival data are typically collected under interval sampling. It refers to a situation when entry into a registry is at the time of the first failure event (e.g., HIV infection) within a calendar time interval, the time of the initiating event (e.g., birth) is retrospectively identified for all the cases in the registry, and subsequently the second failure event (e.g., death) is observed during the follow-up. Sampling bias is induced due to the selection process that the data are collected conditioning on the first failure event occurs within a time interval. Consequently, the …

Modification By Frailty Status Of Ambient Air Pollution Effects On Lung Function In Older Adults In The Cardiovascular Health Study, Sandrah P. Eckel, Thomas A. Louis, Paulo H.M. Chaves, Linda P. Fried, Helene G. Margolis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Older adult susceptibility to air pollution health effects is well-recognized. Advanced age may act as a partial surrogate for conditions associated with aging. The authors investigated whether gerontologic frailty (a clinical health status metric) modified the effects of ambient ozone or particulate matter (PM10) air pollution on lung function in 3382 older adults using 7 years of followup data from the Cardiovascular Health Study (CHS) and the CHS Environmental Factors Ancillary Study. Monthly average pollution and annual frailty assessments were related to up to 3 repeated measurements of lung function using novel cumulative summaries of pollution and frailty histories that …

Reduced Bayesian Hierarchical Models: Estimating Health Effects Of Simultaneous Exposure To Multiple Pollutants, Jennifer F. Bobb, Francesca Dominici, Roger D. Peng

Johns Hopkins University, Dept. of Biostatistics Working Papers

Quantifying the health effects associated with simultaneous exposure to many air pollutants is now a research priority of the US EPA. Bayesian hierarchical models (BHM) have been extensively used in multisite time series studies of air pollution and health to estimate health effects of a single pollutant adjusted for potential confounding of other pollutants and other time-varying factors. However, when the scientific goal is to estimate the impacts of many pollutants jointly, a straightforward application of BHM is challenged by the need to specify a random-effect distribution on a high-dimensional vector of nuisance parameters, which often do not have an …

Population-Wide Model-Free Quantification Of Blood-Brain-Barrier Dynamics In Multiple Sclerosis, Russell T. Shinohara, Ciprian Crainiceanu, Brian Caffo, María Inés Gaitán, Daniel Reich

Johns Hopkins University, Dept. of Biostatistics Working Papers

The processes by which new white matter lesions in multiple sclerosis (MS) develop are only partially understood. Much of this understanding has come through magnetic resonance imaging (MRI) of the human brain. One of the hallmarks of new lesion development in MS is enhancement on T1-weighted MRI scans following the intravenous administration of a gadolinium-based contrast agent that shortens the longitudinal relaxation time of the tissue. This visible enhancement in the MRI results from the opening of the blood-brain barrier and reveals areas of active inflammation. The incidence and number of existing enhancing lesions are common outcome measures used in …

Surrogate Screening Models For The Low Physical Activity Criterion Of Frailty, Sandrah P. Eckel, Karen Bandeen-Roche, Paulo H.M. Chaves, Linda P. Fried, Thomas A. Louis

Johns Hopkins University, Dept. of Biostatistics Working Papers

Background and Aims. Low physical activity, one of five criteria in a validated clinical phenotype of frailty, is assessed by a standardized questionnaire on up to 20 leisure time activities. Because of the time demanded to collect the interview data, it has been challenging to translate to studies other than the Cardiovascular Health Study (CHS), for which it was developed. Considering subsets of activities, we identified and evaluated streamlined surrogate assessment methods and compared them to one implemented in the Women’s Health and Aging Study (WHAS).

Methods. Using data on men and women ages 65 and older from the CHS, …

Estimating Effects By Combining Instrumental Variables With Case-Control Designs: The Role Of Principal Stratification, Russell T. Shinohara, Constantine E. Frangakis, Elizabeth Platz, Konstantinos Tsilidis

Johns Hopkins University, Dept. of Biostatistics Working Papers

The instrumental variable framework is commonly used in the estimation of causal effects from cohort samples. In the case of more efficient designs such as the case-control study, however, the combination of the instrumental variable and complex sampling designs requires new methodological consideration. As the prevalence of Mendelian randomization studies is increasing and the cost of genotyping and expression data can be high, the analysis of data gathered from more cost-effective sampling designs is of prime interest. We show that the standard instrumental variable analysis is not applicable to the case-control design and can lead to erroneous estimation and inference. …

A Spatio-Temporal Approach For Estimating Chronic Effects Of Air Pollution, Sonja Greven, Francesca Dominici, Scott L. Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

Estimating the health risks associated with air pollution exposure is of great importance in public health. In air pollution epidemiology, two study designs have been used mainly. Time series studies estimate acute risk associated with short-term exposure. They compare day-to-day variation of pollution concentrations and mortality rates, and have been criticized for potential confounding by time-varying covariates. Cohort studies estimate chronic effects associated with long-term exposure. They compare long-term average pollution concentrations and time-to-death across cities, and have been criticized for potential confounding by individual risk factors or city-level characteristics.

We propose a new study design and a statistical model, …

Covariate-Adjusted Nonparametric Analysis Of Magnetic Resonance Images Using Markov Chain Monte Carlo, Haley Hedlin, Brian S. Caffo, Ziyad Mahfoud, Susan Spear Bassett

Johns Hopkins University, Dept. of Biostatistics Working Papers

Permutation tests are useful for drawing inferences from imaging data because of their flexibility and ability to capture features of the brain that are difficult to capture parametrically. However, most implementations of permutation tests ignore important confounding covariates. To employ covariate control in a nonparametric setting we have developed a Markov chain Monte Carlo (MCMC) algorithm for conditional permutation testing using propensity scores. We present the first use of this methodology for imaging data. Our MCMC algorithm is an extension of algorithms developed to approximate exact conditional probabilities in contingency tables, logit, and log-linear models. An application of our non-parametric …

Nonlinear Tube-Fitting For The Analysis Of Anatomical And Functional Structures, Jeff Goldsmith, Brian S. Caffo, Ciprian Crainiceanu, Daniel Reich, Yong Du, Craig Hendrix

Johns Hopkins University, Dept. of Biostatistics Working Papers

We are concerned with the estimation of the exterior surface of tube-shaped anatomical structures. This interest is motivated by two distinct scientific goals, one dealing with the distribution of HIV microbicide in the colon and the other with measuring degradation in white-matter tracts in the brain. Our problem is posed as the estimation of the support of a distribution in three dimensions from a sample from that distribution, possibly measured with error. We propose a novel tube-fitting algorithm to construct such estimators. Further, we conduct a simulation study to aid in the choice of a key parameter of the algorithm, …

Learning From Near Misses In Medication Errors: A Bayesian Approach, Jessica A. Myers, Francesca Dominici, Laura Morlock

Johns Hopkins University, Dept. of Biostatistics Working Papers

Medical errors originating in health care facilities are a significant source of preventable morbidity, mortality, and healthcare costs. Voluntary error report systems that collect information on the causes and contributing factors of medi- cal errors regardless of the resulting harm may be useful for developing effective harm prevention strategies. Some patient safety experts question the utility of data from errors that did not lead to harm to the patient, also called near misses. A near miss (a.k.a. close call) is an unplanned event that did not result in injury to the patient. Only a fortunate break in the chain of …

Spatial Misalignment In Time Series Studies Of Air Pollution And Health Data, Roger D. Peng, Michelle L. Bell

Johns Hopkins University, Dept. of Biostatistics Working Papers

Time series studies of environmental exposures often involve comparing daily changes in a toxicant measured at a point in space with daily changes in an aggregate measure of health. Spatial misalignment of the exposure and response variables can bias the estimation of health risk and the magnitude of this bias depends on the spatial variation of the exposure of interest. In air pollution epidemiology, there is an increasing focus on estimating the health effects of the chemical components of particulate matter. One issue that is raised by this new focus is the spatial misalignment error introduced by the lack of …

An Overview Of Observational Sleep Research With Application To Sleep Stage Transitioning, Brian S. Caffo, B. Swihart, A. Laffan, C. Crainiceanu, N. Punjabi

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this manuscript we give an overview of observational sleep research with a particular emphasis on sleep stage transitions. Sleep states represent a categorization of sleep electroencephalogram behavior over the night. We postulate that the rate of transitioning between sleep states is an important predictor of health. This claim is evaluated by comparing subjects with sleep disordered breathing to matched controls.

Model Selection And Health Effect Estimation In Environmental Epidemiology, Francesca Dominici, Chi Wang, Ciprian Crainiceanu, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

In air pollution epidemiology, improvements in statistical analysis tools can translate into significant scientific advances, because of the unfavorable signal-to-noise ratios, and large correlations between exposures and confounders. Therefore, the use of a novel model selection approach in identifying time windows of exposure to pollutants that lead to adverse health effects is important and welcome. However, previous literature has raised concerns about approaches that select a model based on a given data set, and then estimate health effects in the same data assuming that the chosen model is correct. Problems can be particularly severe when: 1) the sample size is …

Is Mri-Based Volume A Mediator Of The Association Of Cumulative Lead Dose With Cognitive Function?, Brian S. Caffo, Sining Chen, Walter Stewart, Karen Bolla, David Yousem, Christos Davatzikos, Brian S. Schwartz

Johns Hopkins University, Dept. of Biostatistics Working Papers

This work considers the pathway through which past occupational lead exposure impacts cognitive function using cross-sectional data. It is motivated by studies linking cumulative lead dose with brain volumes, volumes with cognitive function, and lead dose with cognitive function. It is hypothesized that the brain regions associated with lead mediate a portion of the association between lead dose and cognitive function. The data were derived from an ongoing study of 513 former organolead manufacturing workers. Using MRIs, a novel analysis was performed to investigate Mediation. Volumes associated with cognitive function and lead dose were derived using registered images and used …

Trends In Particulate Matter And Mortality: An Approach To The Assessment Of Unmeasured Confounding, Holly Janes, Francesca Dominici, Scott Zeger

Johns Hopkins University, Dept. of Biostatistics Working Papers

We propose a method for diagnosing confounding bias under a model which links a spatially and temporally varying exposure and health outcome. We decompose the association into orthogonal components, corresponding to distinct spatial and temporal scales of variation. If the model fully controls for confounding, the exposure effect estimates should be equal at the different temporal and spatial scales. We show that the overall exposure effect estimate is a weighted average of the scale-specific exposure effect estimates.

We use this approach to estimate the association between monthly averages of fine particles (PM2.5) over the preceding 12 months and monthly mortality …

Assessing The Unreliability Of The Medical Literature: A Response To "Why Most Published Research Findings Are False", Steven Goodman, Sander Greenland

Johns Hopkins University, Dept. of Biostatistics Working Papers

A recent article in this journal (Ioannidis JP (2005) Why most published research findings are false. PLoS Med 2: e124) argued that more than half of published research findings in the medical literature are false. In this commentary, we examine the structure of that argument, and show that it has three basic components:

1)An assumption that the prior probability of most hypotheses explored in medical research is below 50%.

2)Dichotomization of P-values at the 0.05 level and introduction of a “bias” factor (produced by significance-seeking), the combination of which severely weakens the evidence provided by every design.

3)Use of Bayes …

Forecasting The Global Burden Of Alzheimer's Disease, Ron Brookmeyer, Elizabeth Johnson, Kathryn Ziegler-Graham, H. Michael Arrighi

Johns Hopkins University, Dept. of Biostatistics Working Papers

Background: The goal was to forecast the global burden of Alzheimer’s disease and evaluate the potential impact of interventions that delay disease onset or progression. Methods: A stochastic multi-state model was used in conjunction with U.N. worldwide population forecasts and data from epidemiological studies on risks of Alzheimer’s disease.

Findings: In 2006 the worldwide prevalence of Alzheimer’s disease was 26.6 million. By 2050, prevalence will quadruple by which time 1 in 85 persons worldwide will be living with the disease. We estimate about 43% of prevalent cases need a high level of care equivalent to that of a nursing home. …

A Comparative Analysis Of The Chronic Effects Of Fine Particulate Matter, Sorina E. Eftim, Holly Janes, Aidan Mcdermott, Jonathan M. Samet, Francesca Dominici

Johns Hopkins University, Dept. of Biostatistics Working Papers

The American Cancer Society study (ACS) and the Harvard Six Cities study (SCS) are the two landmark cohort studies for estimating the chronic effects of fine particulate matter PM2.5 on mortality. To date, no comparative analysis of these studies has been carried out using a different study design, study period, data, and modeling approach. In this paper, we estimate the chronic effects of PM on mortality for the period 2000-2002 by using mortality data from Medicare and \PM levels from the National Air Pollution Monitoring Network for the same counties included in the SCS and the ACS. We use a …

Investigating Mediation When Counterfactuals Are Not Metaphysical: Does Sunlight Uvb Exposure Mediate The Effect Of Eyeglasses On Cataracts?, Brian Egleston, Daniel O. Scharfstein, Beatriz Munoz, Sheila West

Johns Hopkins University, Dept. of Biostatistics Working Papers

We investigate the degree to which a reduction in ocular sunlight ultra-violet B (UVB) exposure mediates a relationship between wearing eyeglasses and a decreased risk of cataracts. An estimand is proposed in which causal effects are estimated locally within strata based on potential UVB exposure without glasses and the degree to which glasses use reduces UVB exposure. We take advantage of the structure of the data in which the counterfactual UVB exposures if the participants in the study who wore glasses had not worn glasses are considered observable.

Bivariate Binomial Spatial Modelling Loa Loa Prevalence In Tropical Africa, Ciprian M. Crainiceanu, Peter J. Diggle, Barry Rowlingson

Johns Hopkins University, Dept. of Biostatistics Working Papers

We present a state-of-the-art application of smoothing for dependent bivariate binomial spatial data to Loa loa prevalence mapping in West Africa. This application is special because it starts with the non-spatial calibration of survey instruments, continues with the spatial model building and assessment and ends with robust, tested software that will be used by the field scientists of the World Health Organization for online prevalence map updating. From a statistical perspective several important methodological issues were addressed: (a) building spatial models that are complex enough to capture the structure of the data but remain computationally usable; (b)reducing the computational burden …

Additive Hazards Models With Latent Treatment Effectiveness Lag Time, Ying Qing Chen, Charles A. Rohde, Mei-Cheng Wang

Johns Hopkins University, Dept. of Biostatistics Working Papers

In many clinical trials to evaluate treatment efficacy, it is believed that there may exist latent treatment effectiveness lag times after which medical procedure or chemical compound would be in full effect. In this article, semiparametric regression models are proposed and studied to estimate the treatment effect accounting for such latent lag times. The new models take advantage of the invariance property of the additive hazards model in marginalizing over random effects, so parameters in the models are easy to be estimated and interpreted, while the flexibility without specifying baseline hazard function is kept. Monte Carlo simulation studies demonstrate the …

Estimation And Projection Of Indicence And Prevalence Based On Doubly Truncated Data With Application To Pharmacoepidemiological Databases, Henrik Stovring, Mei-Cheng Wang

Johns Hopkins University, Dept. of Biostatistics Working Papers

Incidences of disease are of primary interest in any epidemiological analysis of disease spread in general populations. Ordinary estimates obtained from follow-up of an initially non-diseased cohort are costly, and so such estimates are not routinely available. In contrast, routine registers exist for many diseases with data on all detected cases within a given calendar time period, but lacking information on non-diseased. In the present work we show how this type of data supplemented with data on the past birth process can be analyzed to yield age specific incidence estimates as well as lifetime prevalence. A non-parametric model is studied …

Estimating Percentile-Specific Causal Effects: A Case Study Of Micronutrient Supplementation, Birth Weight, And Infant Mortality, Francesca Dominici, Scott L. Zeger, Giovanni Parmigiani, Joanne Katz, Parul Christian

Johns Hopkins University, Dept. of Biostatistics Working Papers

In developing countries, higher infant mortality is partially caused by poor maternal and fetal nutrition. Clinical trials of micronutrient supplementation are aimed at reducing the risk of infant mortality by increasing birth weight. Because infant mortality is greatest among the low birth weight infants (LBW) (• 2500 grams), an effective intervention may need to increase the birth weight among the smallest babies. Although it has been demonstrated that supplementation increases the birth weight in a trial conducted in Nepal, there is inconclusive evidence that the supplementation improves their survival. It has been hypothesized that a potential benefit of the treatment …

Ranking Usrds Provider-Specific Smrs From 1998-2001, Rongheng Lin, Thomas A. Louis, Susan M. Paddock, Greg Ridgeway

Johns Hopkins University, Dept. of Biostatistics Working Papers

Provider profiling (ranking, "league tables") is prevalent in health services research. Similarly, comparing educational institutions and identifying differentially expressed genes depend on ranking. Effective ranking procedures must be structured by a hierarchical (Bayesian) model and guided by a ranking-specific loss function, however even optimal methods can perform poorly and estimates must be accompanied by uncertainty assessments. We use the 1998-2001 Standardized Mortality Ratio (SMR) data from United States Renal Data System (USRDS) as a platform to identify issues and approaches. Our analyses extend Liu et al. (2004) by combining evidence over multiple years via an AR(1) model; by considering estimates …