Evaluation of the benchmark dose for point of departure determination for a variety of chemical classes in applied regulatory settings

Repeated-dose studies received by the New Substances Assessment and Control Bureau (NSACB) of Health Canada are used to provide hazard information toward risk calculation. These studies provide a point of departure (POD), traditionally the NOAEL or LOAEL, which is used to extrapolate the quantity of substance above which adverse effects can be expected in humans. This project explored the use of benchmark dose (BMD) modeling as an alternative to this approach for studies with few dose groups. Continuous data from oral repeated-dose studies for chemicals previously assessed by NSACB were reanalyzed using U.S. EPA benchmark dose software (BMDS) to determine the BMD and BMD 95% lower confidence limit (BMDL(05) ) for each endpoint critical to NOAEL or LOAEL determination for each chemical. Endpoint-specific benchmark dose-response levels , indicative of adversity, were consistently applied. An overall BMD and BMDL(05) were calculated for each chemical using the geometric mean. The POD obtained from benchmark analysis was then compared with the traditional toxicity thresholds originally used for risk assessment. The BMD and BMDL(05) generally were higher than the NOAEL, but lower than the LOAEL. BMDL(05) was generally constant at 57% of the BMD. Benchmark provided a clear advantage in health risk assessment when a LOAEL was the only POD identified, or when dose groups were widely distributed. Although the benchmark method cannot always be applied, in the selected studies with few dose groups it provided a more accurate estimate of the real no-adverse-effect level of a substance.     

India’s ‘Missing Women’ and Men’s Sexual Risk Behavior

Although scholars and policymakers have long been concerned with the ??missing women?? of India, little rigorous research has examined the consequences of India??s sex ratio imbalance for young men??s sexual risk behavior and reproductive health. We use data from the third wave of India??s 2005?C2006 National Family and Health Survey to examine the influence of the community female-to-male sex ratio at ages 10?C39 on men??s likelihood of marrying early in life, of engaging in premarital, multi-partnered, and commercial sex, and of contracting a sexually-transmitted disease. We estimate logistic regression models that control for respondents?? demographic and socioeconomic status and that adjust for the clustering of observations within communities. Net of the effects of other characteristics, the female-to-male sex ratio is positively and significantly associated with the likelihood that men marry prior to age 18 and inversely and significantly associated with the odds that men have had intercourse with a commercial sex worker. However, no significant net associations are observed between the sex ratio and the other outcomes. Education, wealth, religious affiliation, caste, and geographic region emerge as significant predictors of Indian men??s sexual risk behaviors.     

Efficient crossover designs in the presence of interactions between direct and carry-over treatment effects

Crossover designs, or repeated measurements designs, are used for experiments in which t treatments are applied to each of n experimental units successively over p time periods. Such experiments are widely used in areas such as clinical trials, experimental psychology and agricultural field trials. In addition to the direct effect on the response of the treatment in the period of application, there is also the possible presence of a residual, or carry-over, effect of a treatment from one or more previous periods. We use a model in which the residual effect from a treatment depends upon the treatment applied in the succeeding period; that is, a model which includes interactions between the treatment direct and residual effects. We assume that residual effects do not persist further than one succeeding period.A particular class of strongly balanced repeated measurements designs with n=t² units and which are uniform on the periods is examined. A lower bound for the A-efficiency of the designs for estimating the direct effects is derived and it is shown that such designs are highly efficient for any number of periods p=2,…,2t.     

Selecting the t-best cells in a multinomial distribution

The problem of selecting the t-best cells in a multinomial distribution with t + k cells, k > 1, 2 <= t is considered under the fixed sample-size indifference zone approach. The least favourable configuration is derived for the usual procedure of selection, for large values of N (the sample size). The result settles Conjecture I (for large N) and Conjecture IV of Chen and Hwang (Commun. Statist. - Theory Meth. 13 (10), 1289-1298, 1984) in the affirmative.     

Model-cum-design-based estimation of the prevalence rate of a disease in a locality using spatial smoothing

In this article, we study the problem of estimating the prevalence rate of a disease in a geographical area, based on data collected from a sample of locations within this area. If there are several locations with zero incidence of the disease, the usual estimators are not suitable and so we develop a new estimator, together with an unbiased estimator of its variance, which may be appropriately used in such situations. An application of this estimator is illustrated with data from a large-scale survey, which was carried out in the city of Kolkata, India, to estimate the prevalence rate of stroke. We show that spatial modelling may be used to smooth the observed data before applying our proposed estimator. Our computations show that this smoothing helps to reduce the coefficient of variation and such a model-cum-design-based procedure is useful for estimating the prevalence rate. This method may of course be used in other similar situations.     

Optimal crossover designs when carryover effects are proportional to direct effects

Crossover designs are used for a variety of different applications. While these designs have a number of attractive features, they also induce a number of special problems and concerns. One of these is the possible presence of carryover effects. Even with the use of washout periods, which are for many applications widely accepted as an indispensable component, the effect of a treatment from a previous period may not be completely eliminated. A model that has recently received renewed attention in the literature is the model in which first-order carryover effects are assumed to be proportional to direct treatment effects. Under this model, assuming that the constant of proportionality is known, we identify optimal and efficient designs for the direct effects for different values of the constant of proportionality. We also consider the implication of these results for the case that the constant of proportionality is not known.     

Coverage with k-transmitters in the presence of obstacles

For a fixed integer k≥0, a k-transmitter is an omnidirectional wireless transmitter with an infinite broadcast range that is able to penetrate up to k “walls”, represented as line segments in the plane. We develop lower and upper bounds for the number of k-transmitters that are necessary and sufficient to cover a given collection of line segments, polygonal chains and polygons.     

Residential mobility and the onset of adolescent sexual activity

Data from almost 5,000 adolescent respondents to the National Longitudinal Study of Adolescent Health (Add Health) are used to examine the mechanisms that transmit the facilitative effect of residential mobility on the timing of the transition to first premarital sexual intercourse. Adolescents who have recently moved are approximately one third more likely than nonmobile adolescents to experience first premarital intercourse between the first two waves of Add Health. We find that much of the difference between adolescent movers and stayers in the onset of sexual activity is attributable to the greater propensity for delinquency and the weaker academic performance among members of movers’ school‐based friendship networks. Adolescents’ own delinquent behavior and academic performance also help to mediate the association between residential mobility and the transition to first intercourse.     

RESIDENTIAL MOBILITY AND ATTEMPTED SUICIDE AMONG ADOLESCENTS: An Individual-Level Analysis

Building on the Durkheimian legacy's emphasis on social integration as a determinant of suicidal behavior, many macrolevel studies have observed an association between aggregate rates of geographical mobility and suicide, but little research has explored this connection at the individual level. We use data from 9,594 respondents who participated in two waves of the National Longitudinal Study of Adolescent Health to examine the effect of recent residential mobility on attempted suicide one year later and to explore the mechanisms that potentially transmit this effect. We find that among adolescent girls, recent movers are about 60 percent more likely than nonmovers to report having attempted suicide during the following year and that this difference cannot be readily explained by mover versus nonmover differences in preexisting demographic and family background characteristics. Some of the apparent effect of residential mobility on females' risk of attempting suicide operates through higher rates of victimization and delinquency, lower levels of school attachment, higher rates of social isolation, and a tendency for movers to associate with peers who exhibit delinquent behaviors and who themselves have attempted suicide. In contrast, we find no evidence that mobile female adolescents' deficit of parental social capital or lower levels of school engagement can account for the difference in attempted suicide risk between movers and nonmovers. We also find that residential mobility is not significantly associated with suicide attempts among adolescent males.     

Optimally robust credible sets with a class of priors

We determine a credible set A   that is the “best” with respect to the variation of the prior distribution in a neighborhood Γ$\Gamma$ of the starting prior _π0(θ)${\pi }_0(\theta )$. Among the class of sets with credibility γ$\gamma$ under _π0${\pi }_0$, the “optimally robust” set will be the one which maximizes the minimum probability of including θ$\theta$ as the prior varies over Γ$\Gamma$. This procedure is also Γ-minimax$\Gamma \text{-minimax}$ with respect to the risk function, probability of non-inclusion. We find the optimally robust credible set for three neighborhood classes Γ$\Gamma$, the ε-contamination$\epsilon \text{-contamination}$ class, the density ratio class and the density bounded class. A consequence of this investigation is that the maximum likelihood set is seen to be an optimal credible set from a robustness perspective.