Discrete Scale Models for Survival–Sacrifice Experiments

Analyses of carcinogenicity experiments involving occult (hidden) tumours are usually based on cause-of-death information or the results of many interim sacrifices. A simple compartmental model is described that does not involve the cause of death. The method of analysis requires only one interim sacrifice, in addition to the usual terminal kill, to ensure that the tumour incidence rates can be estimated. One advantage of the approach is demonstrated in the analysis of glomerulosclerosis following exposure to ionizing radiation. Although the semiparametric model involves fewer parameters, estimates of key functions derived in this analysis are similar to those obtained previously by using a nonparametric method that involves many more parameters.     

Cox regression analysis in presence of collinearity: an application to assessment of health risks associated with occupational radiation exposure

This paper considers the analysis of time to event data in the presence of collinearity between covariates. In linear and logistic regression models, the ridge regression estimator has been applied as an alternative to the maximum likelihood estimator in the presence of collinearity. The advantage of the ridge regression estimator over the usual maximum likelihood estimator is that the former often has a smaller total mean square error and is thus more precise. In this paper, we generalized this approach for addressing collinearity to the Cox proportional hazards model. Simulation studies were conducted to evaluate the performance of the ridge regression estimator. Our approach was motivated by an occupational radiation study conducted at Oak Ridge National Laboratory to evaluate health risks associated with occupational radiation exposure in which the exposure tends to be correlated with possible confounders such as years of exposure and attained age. We applied the proposed methods to this study to evaluate the association of radiation exposure with all-cause mortality.     

Estimating percentile-specific treatment effects in counterfactual models: a case-study of micronutrient supplementation, birth weight and infant mortality

Summary.  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 (LBW) infants (2500 g or under), an effective intervention increases the birth weight among the smallest babies. The paper defines population and counterfactual parameters for estimating the treatment effects on birth weight and on survival as functions of the percentiles of the birth weight distribution. We use a Bayesian approach with data augmentation to approximate the posterior distributions of the parameters, taking into account uncertainty that is associated with the imputation of the counterfactuals. This approach is particularly suitable for exploring the sensitivity of the results to unverifiable modelling assumptions and other prior beliefs. We estimate that the average causal effect of the treatment on birth weight is 72 g (95% posterior regions 33–110 g) and that this causal effect is largest among the LBW infants. Posterior inferences about average causal effects of the treatment on birth weight are robust to modelling assumptions. However, inferences about causal effects for babies at the tails of the birth weight distribution can be highly sensitive to the unverifiable assumption about the correl-ation between the observed and the counterfactuals birth weights. Among the LBW infants who have a large causal effect of the treatment on birth weight, we estimate that a baby receiving the treatment has 5% less chance of death than if the same baby had received the control. Among the LBW infants, we found weak evidence supporting an additional beneficial effect of the treatment on mortality independent of birth weight.     

Bayesian methods for the cross-design synthesis of epidemiological and toxicological evidence

Summary.  Systematic review and synthesis (meta-analysis) methods are now increasingly used in many areas of health care research. We investigate the potential usefulness of these methods for combining human and animal data in human health risk assessment of exposure to environmental chemicals. Currently, risk assessments are often based on narrative review and expert judgment, but systematic review and formal synthesis methods offer a more transparent and rigorous approach. The method is illustrated by using the example of trihalomethane exposure and its possible association with low birth weight. A systematic literature review identified 13 relevant studies (five epidemiological and eight toxicological). Study-specific dose–response slope estimates were obtained for each of the studies and synthesized by using Bayesian meta-analysis models. Sensitivity analyses of the results obtained to the assumptions made suggest that some assumptions are critical. It is concluded that systematic review methods should be used in the synthesis of evidence for environmental standard setting, that meta-analysis will often be a valuable approach in these contexts and that sensitivity analyses are an important component of the approach whether or not formal synthesis methods (such as systematic review and meta-analysis) are used.     

Impact of additive covariate error on linear model

Abstract

We consider effect of additive covariate error on linear model in observational (radiation epidemiology) study for exposure risk. Additive dose error affects dose-response shape under general linear regression settings covering identity-link GLM type models and linear excess-relative-risk grouped-Poisson models. Under independent error, dose distribution that log of dose density is up to quadratic polynomial on an interval (the log-quadratic density condition), normal, exponential, and uniform distributions, is the condition for linear regression calibration. Violation of the condition can result low-dose-high-sensitivity model from linear no-threshold (LNT) model by the dose error. Power density is also considered. A published example is given.     

Joint distribution of simultaneous exposures to several carcinogens in a case–control study: sample size determination

Consider a population of individuals who are free of a disease under study, and who are exposed simultaneously at random exposure levels, say X,Y,Z,… to several risk factors which are suspected to cause the disease in the populationm. At any specified levels X=x, Y=y, Z=z, …, the incidence rate of the disease in the population ot risk is given by the exposure–response relationship r(x,y,z,…) = P(disease|x,y,z,…). The present paper examines the relationship between the joint distribution of the exposure variables X,Y,Z, … in the population at risk and the joint distribution of the exposure variables U,V,W,… among cases under the linear and the exponential risk models. It is proven that under the exponential risk model, these two joint distributions belong to the same family of multivariate probability distributions, possibly with different parameters values. For example, if the exposure variables in the population at risk have jointly a multivariate normal distribution, so do the exposure variables among cases; if the former variables have jointly a multinomial distribution, so do the latter. More generally, it is demonstrated that if the joint distribution of the exposure variables in the population at risk belongs to the exponential family of multivariate probability distributions, so does the joint distribution of exposure variables among cases. If the epidemiologist can specify the differnce among the mean exposure levels in the case and control groups which are considered to be clinically or etiologically important in the study, the results of the present paper may be used to make sample size determinations for the case–control study, corresponding to specified protection levels, i.e., size α and 1–β of a statistical test. The multivariate normal, the multinomial, the negative multinomial and Fisher's multivariate logarithmic series exposure distributions are used to illustrate our results.     

Nonparametric estimation of the hazard function by using a model selection method: estimation of cancer deaths in Hiroshima atomic bomb survivors

Summary.  Controversy has intensified regarding the death-rate from cancer that is induced by a dose of radiation. In the models that are usually considered the hazard function is an increasing function of the dose of radiation. Such models can mask local variations. We consider the models of excess relative risk and of absolute risk and propose a nonparametric estimation of the effect of the dose by using a model selection procedure. This estimation deals with stratified data. We approximate the function of the dose by a collection of splines and select the best one according to the Akaike information criterion. In the same way between the models of excess relative risk or excess absolute risk, we choose the model that best fits the data. We propose a bootstrap method for calculating a pointwise confidence interval of the dose function. We apply our method for estimating the solid cancer and leukaemia death hazard functions to Hiroshima.     

Identifying radon-prone building typologies by marginal modelling

Radon is a naturally occurring decay product of uranium known to be the main contributor to natural background radiation exposure. It has been established that the health risk related to radon exposure is lung cancer. In fact, radon is considered to be a major leading cause of lung cancer, second only to smoking. In this paper, we identified building typologies that affect the probability of detecting indoor radon concentration above reference values, using the data collected within two monitoring campaigns recently conducted in Northern Italy. This information is fundamental both in prevention, i.e. when the construction of a new building is planned and in mitigation, i.e. when a high concentration detected inside buildings has to be reduced. A spatial regression approach for binary data was adopted for this goal where some relevant covariates on the soil were retrieved by linking external spatial databases.     

Spatial smoothing of low birth weight rate in Bangladesh using Bayesian hierarchical model

The term low birth weight refers an event where a newborn baby has a weight that is less than 2500?g. This is an essential indicator while the interest is in public health issues such as infant mortality, maternal complications, and antenatal care, etc. of a country, particularly, for a developing country like Bangladesh. The regional development programs are in the current priority list of Bangladesh government and other policy makers. Many of such regional development programs may need the spatial distribution of relative risk for low birth weight that can be obtained by mapping the risks over small area domains like the districts of Bangladesh. This study aims to find whether is there any spatial dependence among the relative risks of low birth weight for the districts of Bangladesh. This has been investigated using Moran's I statistic and a significant spatial dependence in the relative risks was found. Then, attempt has been made to rediscover the spatial distribution based on the idea of spatial smoothing. A Bayesian hierarchical model is used considering percent received antenatal care and female labor force participation as covariates to smooth the observed relative risks of low birth weight in 64 districts of Bangladesh. Revised spatial distribution taking the spatial dependence under consideration through intrinsic conditional autoregressive model is derived and showed in choropleth map along with its different behaviors.     

A geostatistical approach to define guidelines for radon prone area identification

Radon is a natural radioactive gas known to be the main contributor to natural background radiation exposure and the major leading cause of lung cancer second to smoking. Indoor radon concentration levels of 200 and 400 Bq/m³ are reference values suggested by the 90/143/Euratom recommendation, above which mitigation measures should be taken in new and old buildings, respectively, to reduce exposure to radon. Despite this international recommendation, Italy still does not have mandatory regulations or guidelines to deal with radon in dwellings. Monitoring surveys have been undertaken in a number of western European countries in order to assess the exposure of people to this radioactive gas and to identify radon prone areas. However, such campaigns provide concentration values in each single dwelling included in the sample, while it is often necessary to provide measures of the pollutant concentration which refer to sub-areas of the region under study. This requires a realignment of the spatial data from the level at which they are collected (points) to the level at which they are necessary (areas). This is known as change of support problem.In this paper, we propose a methodology based on geostatistical simulations in order to solve this problem and to identify radon prone areas which may be suggested for national guidelines.     

Unmasking the Trend Sought by Jonckheere-Type Tests for Right-Censored Data

Medical and epidemiological studies often involve groups of subjects associated with increasing levels of exposure to a risk factor. Survival of the groups is expected to follow the same order as the level of exposure. Formal tests for this trend fall into the regression framework if one knows what function of exposure to use as a covariate. When unknown, a linear function of exposure level is often used. Jonckheere-type tests for trend have generated continued interest largely because they do not require specification of a covariate. This paper shows that the Jonckheere-type test statistics are special cases of a generalized linear rank statistic with time-dependent covariates which unfortunately depend on the initial group sizes and censoring distributions. Using asymptotic relative efficiency calculations, the Jonckheere tests are compared to standard linear rank tests based on a linear covariate over a spectrum of shapes for the true trend.     

The National Wilms Tumor Study: a 40 year perspective

The National Wilms Tumor Study (NWTS) was the first pediatric intergroup clinical research unit in North America. It was thus able to collect data concerning children with malignant kidney tumors from each of the then-extant childhood cancer cooperative study groups. Enough patients—about 350 per year—could thus be gathered to study the nature and clinical characteristics of the various kidney malignant tumors of childhood. It also enabled randomized trials of comparative treatment regimens, patients stratified following stipulated risk criteria. The result has been a steadily increasing two-year survival rate to the 90% level while at the same time modulating the intensity of therapy according to well-defined needs. For example, routine post-operative radiation therapy, damaging to normal as well as neoplastic tissues, has been largely eliminated. The proportion of patients given doxorubicin, a cardiotoxic drug, also has been curtailed. These two therapies are now restricted to the 30% of patients who have more advanced or more aggressive disease. All this has been driven to meet the challenge inherent in the motto of pediatric oncology: “Cure is not enough”; that is, the cured child of to-day must not become the chronically ill adult of tomorrow, suffering from the delayed complications secondary to unnecessary, toxic therapies.     

Disaggregated spatial modelling for areal unit categorical data

Summary.  We consider joint spatial modelling of areal multivariate categorical data assuming a multiway contingency table for the variables, modelled by using a log-linear model, and connected across units by using spatial random effects. With no distinction regarding whether variables are response or explanatory, we do not limit inference to conditional probabilities, as in customary spatial logistic regression. With joint probabilities we can calculate arbitrary marginal and conditional probabilities without having to refit models to investigate different hypotheses. Flexible aggregation allows us to investigate subgroups of interest; flexible conditioning enables not only the study of outcomes given risk factors but also retrospective study of risk factors given outcomes. A benefit of joint spatial modelling is the opportunity to reveal disparities in health in a richer fashion, e.g. across space for any particular group of cells, across groups of cells at a particular location, and, hence, potential space–group interaction. We illustrate with an analysis of birth records for the state of North Carolina and compare with spatial logistic regression.     

Risk patterns in drug safety study using relative times by accelerated failure time models when proportional hazards assumption is questionable: an illustrative case study of cancer risk of patients on glucose‐lowering therapies

Observational drug safety studies may be susceptible to confounding or protopathic bias. This bias may cause a spurious relationship between drug exposure and adverse side effect when none exists and may lead to unwarranted safety alerts. The spurious relationship may manifest itself through substantially different risk levels between exposure groups at the start of follow‐up when exposure is deemed too short to have any plausible biological effect of the drug. The restrictive proportional hazards assumption with its arbitrary choice of baseline hazard function renders the commonly used Cox proportional hazards model of limited use for revealing such potential bias. We demonstrate a fully parametric approach using accelerated failure time models with an illustrative safety study of glucose‐lowering therapies and show that its results are comparable against other methods that allow time‐varying exposure effects. Our approach includes a wide variety of models that are based on the flexible generalized gamma distribution and allows direct comparisons of estimated hazard functions following different exposure‐specific distributions of survival times. This approach lends itself to two alternative metrics, namely relative times and difference in times to event, allowing physicians more ways to communicate patient's prognosis without invoking the concept of risks, which some may find hard to grasp. In our illustrative case study, substantial differences in cancer risks at drug initiation followed by a gradual reduction towards null were found. This evidence is compatible with the presence of protopathic bias, in which undiagnosed symptoms of cancer lead to switches in diabetes medication. Copyright © 2015 John Wiley & Sons, Ltd.     

Sovereign rescheduling probabilities in emerging markets: a comparison with credit rating agencies’ ratings

This study estimates default probabilities of 124 emerging countries from 1981 to 2002 as a function of a set of macroeconomic and political variables. The estimated probabilities are then compared with the default rates implied by sovereign credit ratings of three major international credit rating agencies (CRAs) – Moody's Investor's Service, Standard & Poor's and Fitch Ratings. Sovereign debt default probabilities are used by investors in pricing sovereign bonds and loans as well as in determining country risk exposure. The study finds that CRAs usually underestimate the risk of sovereign debt as the sovereign credit ratings from rating agencies are usually too optimistic.     

Analysis of the Bovine Spongiform Encephalopathy Maternal Cohort Study: Evidence for Direct Maternal Transmission

In an initial exploratory analysis of the bovine spongiform encephalopathy (BSE) maternal cohort study data we demonstrate several confounding effects in the study design. Given these effects, we assess a variety of statistical models to determine the relative contributions of direct maternal transmission of the aetiological agent of BSE and of genetic susceptibility to the observed maternally enhanced risk of BSE in the offspring of affected dams. To control for the substantial between-herd variation in the risk of exposure to the BSE agent, it is essential that analyses take into account the matched pair structure of the data. Maternal exposure is estimated to be most important in animals born within 150 days of disease onset in their dams. The analysis of a full survival likelihood model indicates that the hypothesis of maternal transmission with no genetic variation in susceptibility fits the data significantly better than the hypothesis of genetically variable susceptibility with no maternal transmission. However, models incorporating both maternal transmission and genetically variable susceptibility fit the data significantly better than pure maternal transmission models. Although genetic susceptibility cannot be excluded as the cause of the cohort study results in the absence of detailed genotyping, the analysis of these study data suggest that low level maternal transmission of BSE is, at least in part, responsible for the significantly enhanced risk of BSE in the offspring of affected dams. Similar results indicating significant maternal transmission in the later stages of the dam incubation period are obtained from the independent analysis of data on the dam–offspring relationships among confirmed BSE cases.     

A NOTE ON THE DEMOGRAPHIC IMPACT OF CONTRACEPTION IN A MATHEMATICAL MODEL OF HUMAN REPRODUCTION

The application of mathematical models of human reproduction to the study of reproductive behaviour as a function of contraceptive behaviour was pioneered by Perrin and Sheps (1963). More recent work in this area continues to focus on an examination of the birth rate as the principal dependent variable. This note suggests an alternative procedure for studying the demographic impact of contraception through the analysis of birth intervals. A mathematical model is formulated for the waiting time between successive live births, and a procedure is described for incorporating into the model certain contraceptive parameters. A controlled experiment is then performed to determine the effect of these parameters on expected child spacing patterns.     

Estimating driver crash risks based on the extended Bradley–Terry model: an induced exposure method

Quantifying driver crash risks has been difficult because the exposure data are often incompatible with crash frequency data. Induced exposure methods provide a promising idea that a relative measurement of driver crash risks can be derived solely from crash frequency data. This paper describes an application of the extended Bradley–Terry model for paired preferences to estimating driver crash risks. We estimate the crash risk for driver groups defined by driver–vehicle characteristics from log-linear models in terms of a set of relative risk scores by using only crash frequency data. Illustrative examples using police-reported crash data from Hawaii are presented.     

Methods for Quantitative Risk Assessment Using Occupational Studies

Although carcinogenic risk assessment is frequently based on animal bioassay data, occupational studies are generally considered the best source of data for quantitative risk estimation. The model selected for use with occupational study data is required to extrapolate on age, exposure level, and temporal exposure pattern. Relative and absolute risk models are examined, as are alternatives for the definition of a dose (exposure) variable. The models express disease incidence as a function of the chosen exposure variable and convert incidence into estimates of lifetime risk. In this form, predictions of the models can be compared. The methods are illustrated using three examples: arsenic exposure and respiratory cancer, leukemia associated with benzene exposure, and asbestos-induced mesothelioma.     

Bayesian Spatial Analysis for the Evaluation of Breast Cancer Detection Methods

This study investigated the impact of spatial location on the effectiveness of population‐based breast screening in reducing breast cancer mortality compared to other detection methods among Queensland women. The analysis was based on linked population‐based datasets from BreastScreen Queensland and the Queensland Cancer Registry for the period of 1997–2008 for women aged less than 90 years at diagnosis. A Bayesian hierarchical regression modelling approach was adopted and posterior estimation was performed using Markov Chain Monte Carlo techniques. This approach accommodated sparse data resulting from rare outcomes in small geographic areas, while allowing for spatial correlation and demographic influences to be included. A relative survival model was chosen to evaluate the relative excess risk for each breast cancer related factor. Several models were fitted to examine the influence of demographic information, cancer stage, geographic information and detection method on women's relative survival. Overall, the study demonstrated that including the detection method and geographic information when assessing the relative survival of breast cancer patients helped capture unexplained and spatial variability. The study also found evidence of better survival among women with breast cancer diagnosed in a screening program than those detected otherwise, as well as lower risk for those residing in a more urban or socio‐economically advantaged region, even after adjusting for tumour stage, environmental factors and demographics. However, no evidence of dependency between method of detection and geographic location was found. This project provides a sophisticated approach to examining the benefit of a screening program while considering the influence of geographic factors.