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AbstractThe US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, concerning the effects of genes and environment on cancer incidence. One likely goal of these efforts will be generate a large population-based case-control series for which a number of candidate genes will be investigated using SNP haplotype as well as genotype analysis. The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression. Our interest is to develop and evaluate extensions of methods, based on haplotype imputation, that have been recently described (Schaid et al., Am J Hum Genet, 2002, and Zaykin et al., Hum Hered, 2002) as providing score tests of the null hypothesis of no effect of SNP haplotypes upon risk, which may be used for more complex tasks, such as providing confidence intervals, and tests of equivalence of haplotype-specific risks in two or more separate populations. In order to do so we (1) develop a cohort approach towards odds ratio analysis by expanding the E-M algorithm to provide maximum likelihood estimates of haplotype-specific odds ratios as well as genotype frequencies; (2) show how to correct the cohort approach, to give essentially unbiased estimates for population-based or nested case-control studies by incorporating the probability of selection as a case or control into the likelihood, based on a simplified model of case and control selection, and (3) finally, in an example data set (CYP17 and breast cancer, from the Multiethnic Cohort Study) we compare likelihood-based confidence interval estimates from the two methods with each other, and with the use of the single-imputation approach of Zaykin et al. applied under both null and alternative hypotheses. We conclude that so long as haplotypes are well predicted by SNP genotypes (we use the R2h criteria of Stram et al. [1]) the differences between the three methods are very small and in particular that the single imputation method may be expected to work extremely well.Copyright © 2003 S. Karger AG, Basel

The emergence of rabies among terrestrial wildlife poses increasing but poorly defined risks to people. In particular, events leading to human exposure to rabies virus via mammalian reservoirs remain elusive. Thus, we determined those risk factors associated with human exposure to rabies-positive animals during a raccoon rabies epizootic in Connecticut. Existing passive surveillance data on animal rabies tests in Connecticut from 1991 through 1994 were evaluated for demographic, ecological, and behavioral characteristics of human exposure. Of 2,525 rabies-positive terrestrial animals identified, human contact was reported on 556 occasions (22%) and involved at least 939 individuals. The annual incidence of exposure rose from none during 1985–1990 to 66 in 1991 and then averaged 291 during 1992–1994. Exposure was most often indirect in nature, involved a rabies-positive raccoon, was mediated through a domestic animal, and occurred most frequently either near or inside the home. These results suggest that human exposure to rabid animals represents a significant, reemerging public health concern in the United States. Analysis of the epizootiology of rabies infection and of individual exposure risks could reduce inappropriate administration of rabies postexposure prophylaxis, as well as inform other proposed interventions.

OBJECTIVE:To examine the impact of fractures on measured physical performance and to assess whether specific fractures have unique sequelae.

The results of 112 children with neuroblastoma treated at the Memorial Sloan-Kettering Cancer Center between 1949 and 1980 were analyzed. Of these children, 58 were 0–11 months old and 54 were 12–23 months old and there was a median follow-up of 111 months. All 10 patients with Stage I are alive, 21/27 with Stages II and III (78 ) are alive, 5/67 patients (7) with Stage IV are alive, and 7/8 patients with Stage IVS are alive. Age of the children is an independent prognostic factor. The survival of infants with Stage IV is significantly better than it is for older children of the same stage. Two of 15 infants in Stages II and III died, both of early complications, whereas 4/12 older children with the same stages died. Minimal individualized treatment is recommended for children 0–11 months old who have localized and Stage IVS neuroblastoma.

Articles published from 1805 to 1815 in the Transactions of the Royal Society of Edinburghreflect a rapidly emerging and meticulous empiricism in the study of earth history; an empiricism directed principally toward an understanding of James Hutton's notions about cyclical, igneous-based, earth processes. One obvious focus for this detailed testing was Hutton's disagreement with Werner over the origin of basalt, which was most carefully explored in the laboratory studies of Sir James Hall and Robert Kennedy. However the geological field observations of Sir George Mackenzie, Lord Webb Seymour, John Playfair and other Society members seemed also to play a most important role in deciphering the Huttonian logic.Hall, following Lavoisier but in disagreement with Hutton, repeatedly emphasized that a more rigorous experimental micro-chemistry would eventually result in a more fundamentally sound macrogeology. In a number of papers read before the Royal Society it was obvious that Hall and his colleagues were indebted to Hutton for his demanding brand of field empiricism, which they acclaimed as a break with the less rigorous 18th century cosmologies, but Hutton was definitely not venerated. Certain Huttonian conclusions were verified but others were severely compromised not only by the results of Hall's fusion experiments but also by numerous field observations especially of Alpine geomorphic features. Indeed, attempting to understand the scale of geological processes through their subsequent effects appears at times to have been a more fundamental pursuit than a continual chorus of fire versus water.Obscured perhaps by the studies of subsequent generations these turn-of-the-century geological controversies were so enriched by empirical fervor that even this brief perusal of the Transactionscannot fail to impress us with the high level of imaginative experimentation devised by members of the Society, experimentation, however, resulting in large part from the Huttonian legacy.

Communities of Paleozoic shelf invertebrates underwent varied rates of change in faunal composition. Notable changes took place during Late Devonian-Early Mississippian time and were most noticeable in offshore brachiopod-dominated communities. Near-shore molluscan communities remained relatively stable throughout the Paleozoic.

Levels of dehydroepiandrosterone sulfate (DHEA-S), the most abundant circulating sex steroid prohormone, decrease progressively with age. It has been suggested that its decline with aging may be associated with increasing risk of cardiovascular disease (CVD). A number of investigators have hypothesized that low DHEA-S levels increase the risk of CVD and all-cause mortality. However, results have not been consistent in all studies, especially among women, and the role of DHEA-S in CVD risk in women is controversial.