Potential motion related bias in the worn dosimeter measurements of two childhood leukemia studies

Time averaged field measurements produced by a Positron dosimeter worn by study subjects was the primary method of exposure evaluation in two Canadian studies of childhood leukemia and AC magnetic field exposure. Statistically significant but mutually contradictory results obtained in the two studies, done in different locales but under similar study conditions, have not been explained. This report examines operational features of the Positron meter, including an unanticipated sensitivity to wearer motion. If the convalescent cases studied were less active than their healthy controls, as one might expect, then the meter's characteristic responses to motion, particularly as they would affect case-control distributions above and below the different referent group cutpoints used in the two studies, could help to explain both the unexpected inverse risks reported in the larger study and the unusually high risks reported in the smaller study.     

Semiparametric regression modeling with mixtures of Berkson and classical error, with application to fallout from the Nevada test site

We construct Bayesian methods for semiparametric modeling of a monotonic regression function when the predictors are measured with classical error. Berkson error, or a mixture of the two. Such methods require a distribution for the unobserved (latent) predictor, a distribution we also model semiparametrically. Such combinations of semiparametric methods for the dose response as well as the latent variable distribution have not been considered in the measurement error literature for any form of measurement error. In addition, our methods represent a new approach to those problems where the measurement error combines Berkson and classical components. While the methods are general, we develop them around a specific application, namely, the study of thyroid disease in relation to radiation fallout from the Nevada test site. We use this data to illustrate our methods, which suggest a point estimate (posterior mean) of relative risk at high doses nearly double that of previous analyses but that also suggest much greater uncertainty in the relative risk.     

Combining complete multivariate outcomes with incomplete covariate information: a latent class approach

This work was motivated by the need to combine outcome information from a reference population with risk factor information from a screened subpopulation in a setting where the analytic goal was to study the association between risk factors and multiple binary outcomes. To achieve such an analytic goal, this article proposes a two-stage latent class procedure that first summarizes the commonalities among outcomes using a reference population sample, then analyzes the association between outcomes and risk factors. It develops a pseudo-maximum likelihood approach to estimating model parameters. The performance of the proposed method is evaluated in a simulation study and in an illustrative analysis of data from the Women's Health and Aging Study, a recent investigation of the causes and course of disability in older women. Combining information in the proposed way is found to improve both accuracy and precision in summarizing multiple categorical outcomes, which effectively diminishes ambiguity and bias in making risk factor inferences.     

Control for confounding in the presence of measurement error in hierarchical models

Hierarchical modeling is becoming increasingly popular in epidemiology, particularly in air pollution studies. When potential confounding exists, a multilevel model yields better power to assess the independent effects of each predictor by gathering evidence across many sub-studies. If the predictors are measured with unknown error, bias can be expected in the individual substudies, and in the combined estimates of the second-stage model. We consider two alternative methods for estimating the independent effects of two predictors in a hierarchical model. We show both analytically and via simulation that one of these gives essentially unbiased estimates even in the presence of measurement error, at the price of a moderate reduction in power. The second avoids the potential for upward bias, at the price of a smaller reduction in power. Since measurement error is endemic in epidemiology, these approaches hold considerable potential. We illustrate the two methods by applying them to two air pollution studies. In the first, we re-analyze published data to show that the estimated effect of fine particles on daily deaths, independent of coarse particles, was downwardly biased by measurement error in the original analysis. The estimated effect of coarse particles becomes more protective using the new estimates. In the second example, we use published data on the association between airborne particles and daily deaths in 10 US cities to estimate the effect of gaseous air pollutants on daily deaths. The resulting effect size estimates were very small and the confidence intervals included zero.     

Monitoring surgical performance using risk-adjusted cumulative sum charts

The cumulative sum (CUSUM) procedure is a graphical method that is widely used for quality monitoring in industrial settings. More recently it has been used to monitor surgical outcomes whereby it 'signals' if sufficient evidence has accumulated that there has been a change in the surgical failure rate. A limitation of the standard CUSUM procedure in this context is that since it is simply based on the observed surgical outcomes, it may signal as a result of changes in the referral pattern, such as an increased proportion of high-risk patients, rather than due to a change in the actual surgical performance. We describe a new CUSUM procedure that adjusts for each patient's pre-operative risk of surgical failure through the use of a likelihood-based scoring method. The procedure is therefore ideally suited for settings where there is a variable mix of patients over time.     

A retrospective assessment of the accuracy of the paternity inference program CERVUS

CERVUS is a Windows-based software package written to infer paternity in natural populations. It offers advantages over exclusionary-based methods of paternity inference in that multiple nonexcluded males can be statistically distinguished, laboratory typing error is considered and statistical confidence is determined for assigned paternities through simulation. In this study we use a panel of 84 microsatellite markers to retrospectively determine the accuracy of statistical confidence when CERVUS was used to infer paternity in a population of red deer (Cervus elaphus). The actual confidence of CERVUS-assigned paternities was not significantly different from that predicted by simulation.     

Modeling markers of disease progression by a hidden Markov process: application to characterizing CD4 cell decline

Multistate models have been increasingly used to model natural history of many diseases as well as to characterize the follow-up of patients under varied clinical protocols. This modeling allows describing disease evolution, estimating the transition rates, and evaluating the therapy effects on progression. In many cases, the staging is defined on the basis of a discretization of the values of continuous markers (CD4 cell count for HIV application) that are subject to great variability due mainly to short time-scale noise (intraindividual variability) and measurement errors. This led us to formulate a Bayesian hierarchical model where, at a first level, a disease process (Markov model on the true states, which are unobserved) is introduced and, at a second level, the measurement process making the link between the true states and the observed marker values is modeled. This hierarchical formulation allows joint estimation of the parameters of both processes. Estimation of the quantities of interest is performed via stochastic algorithms of the family of Markov chain Monte Carlo methods. The flexibility of this approach is illustrated by analyzing the CD4 data on HIV patients of the Concorde clinical trial.     

Measuring tolerance to herbivory: accuracy and precision of estimates made using natural versus imposed damage

Abstract.— Tolerance to herbivory (the ability of a plant to incur herbivore damage without a corresponding reduction in fitness) can be measured using either naturally occurring or imposed herbivore damage. After briefly reviewing some of the advantages and disadvantages of these approaches, we present calculations describing the degree to which estimates of tolerance will be biased by environmental variables that affect both herbivory and fitness. With naturally occurring herbivory the presence of environmental variables that are correlated with herbivory and fitness will result in biased estimates of tolerance. In contrast, estimates obtained from experiments in which herbivory is artificially imposed will be unbiased; however, under a wide range of parameter values these estimates will be less precise than estimates obtained from experiments in which herbivory is not manipulated.