Inference on cancer screening exam accuracy using population-level administrative data.

This paper develops a model for cancer screening and cancer incidence data, accommodating the partially unobserved disease status, clustered data structures, general covariate effects, and dependence between exams. The true unobserved cancer and detection status of screening participants are treated as latent variables, and a Markov Chain Monte Carlo algorithm is used to estimate the Bayesian posterior distributions of the diagnostic error rates and disease prevalence. We show how the Bayesian approach can be used to draw inferences about screening exam properties and disease prevalence while allowing for the possibility of conditional dependence between two exams. The techniques are applied to the estimation of the diagnostic accuracy of mammography and clinical breast examination using data from the Ontario Breast Screening Program in Canada.

Affinity filtration coupled with capillary-based affinity purification for the isolation of protein complexes.

The isolation of complex macromolecular assemblies at the concentrations required for structural analysis represents a major experimental challenge. Here we present a method that combines the genetic power of site-specific recombination in order to selectively "tag" one or more components of a protein complex with affinity-based rapid filtration and a final step of capillary-based enrichment. This modified form of tandem affinity purification produces highly purified protein complexes at high concentrations in a highly efficient manner. The application of the method is demonstrated for the yeast Arp2/3 heptameric protein complex involved in mediating reorganization of the actin cytoskeleton.

Distinguishing Electron Diffusion and Extraction in Methylammonium Lead Iodide.

Charge diffusion and extraction are crucial steps in the operation of solar cells. Here we show that time-resolved photoluminescence can be used to study electron diffusion in hybrid perovskite films and subsequent transfer to the adjacent electron extraction layer. As diffusion and transfer to the extraction layer are consecutive processes, they can be hard to distinguish, but by exciting from each side of the sample we can separate them and identify which process limits charge extraction. We find that the introduction of a fullerene monolayer between the methylammonium lead iodide (MAPbI3) and the electron-transporting SnO2 layers greatly increases the electron transfer velocity between them to the extent that electron diffusion limits the rate of electron extraction. Our results suggest that increasing the electron diffusion coefficient in MAPbI3 would further enhance the electron extraction rate, which could result in more efficient n-i-p type solar cells.

Mapping cancer risk in southwestern Ontario with changing census boundaries.

Mapping disease risk often involves working with data that have been spatially aggregated to census regions or postal regions, either for administrative reasons or confidentiality. When studying rare diseases, data must be collected over a long time period in order to accumulate a meaningful number of cases. These long time periods can result in spatial boundaries of the census regions changing over time, as is the case with the motivating example of exploring the spatial structure of mesothelioma lung cancer risk in Lambton County and Middlesex County of southwestern Ontario, Canada. This article presents a local-EM kernel smoothing algorithm that allows for the combining of data from different spatial maps, being capable of modeling risk for spatially aggregated data with time-varying boundaries. Inference and uncertainty estimates are carried out with parametric bootstrap procedures, and cross-validation is used for bandwidth selection. Results for the lung cancer study are shown and discussed.

Peralkaline volcanicity on the Eurasia Basin margin.

The Kap Washington Group of post-Palaeozoic explosive volcanic rocks was discovered in 1969 on the north coast of Greenland. Although there have been uncertainties regarding their age and chemical character, they have featured prominently in geotectonic reconstructions of the Arctic regions-in recent interpretations as products of the Yermak hot spot, generated on the Nansen spreading axis during the opening of the Eurasia Basin. We present here new evidence which confirms the volcanicity as end-Cretaceous in age and of peralkaline type. We show that a direct connection with the Yermak hot spot is improbable and infer that the volcanic rocks were generated in a continental extensional rift environment before the break-up of the Laurasian plate in the Arctic. Their age helps to constrain the timing of this poorly understood event.

Thymine addition to ethanol: induction by gamma irradiation.

When thymine in dilute, deaerated, aqueous solution was irradiated with gamma-rays in the presence of ethanol, a high yield of products containing both the thymine and ethanol moieties was obtained. These were shown to be isomers formed by the attack of CH(3)CHOH radicals at the carbon No. 6 position of thymine. A similar reaction was observed with N, N'-dimethylthymine, but O,O'-dimethylthymine did not react. The reaction may be relevant to the resistance of certain cells to ionizing radiation.

Inference for clustered inhomogeneous spatial point processes.

SUMMARY: We propose a method to test for significant differences in the levels of clustering between two spatial point processes (cases and controls) while taking into account differences in their first-order intensities. The key advance on earlier methods is that the controls are not assumed to be a Poisson process. Inference and diagnostics are based around the inhomogeneous K-function with confidence envelopes obtained from either resampling events in a nonparametric bootstrap approach, or simulating new events as in a parametric bootstrap. Methods developed are demonstrated using the locations of adult and juvenile trees in a tropical forest. A simulation study briefly examines the accuracy and power of the inferential procedures.

Quantifying within- and between-animal variation and uncertainty associated with counts of Escherichia coli O157 occurring in naturally infected cattle faeces.

Cattle faeces are considered the most important reservoir for human infection with Escherichia coli O157. We have previously described shedding of E. coli O157 in the faeces of naturally infected cattle cohorts. However, the data require further investigation to quantify the uncertainty and variability in the estimates previously presented. This paper proposes a method for analysing both the presence and the quantity of E. coli O157 in cattle faecal samples, using two isolation procedures, one of which enumerates E. coli O157. The combination of these two measurements, which are fundamentally different in nature and yet measuring a common outcome, has necessitated the development of a novel statistical model for ascertaining the contribution of the various components of variation (both natural and observation induced) and for judging the influence of explanatory variables. Most of the variation within the sampling hierarchy was attributable to multiple samples from the same animal. The contribution of laboratory-level variation was found to be low. After adjusting for fixed and random effects, short periods of increased intensity of shedding were identified in individual animals. We conclude that within-animal variation is greater than between animals over time, and studies aiming to elucidate the dynamics of shedding should focus resources, sampling more within than between animals. These findings have implications for the identification of persistent high shedders and for assessing their role in the epidemiology of E. coli O157 in cattle populations. The development of this non-standard statistical model may have many applications to other microbial count data.

Estimation of screening sensitivity and sojourn time from an organized screening program.

Regular screening with mammography is widely recommended to reduce breast cancer mortality. However, whether breast screening does more harm than good has long been debated. Since a full evaluation of the effect on mortality could take 10-15 years in order to provide a reliable estimate of the eventual benefits and harms, it is unrealistic to expect each new modification of a screening technique to be evaluated in this way. Therefore, one needs to rapidly estimate suitable measures of the screening effect. In this paper, two measures of interest, the length of the pre-clinical state and the screening false negative rate, are discussed. A procedure is proposed to model the pre-clinical disease state duration, the false negative rate of the screening exam, and the underlying incidence rate in the screened population. We applied the model to data from the Ontario Breast Screening Program in Canada. Our results suggest that the mean preclinical duration is longer than 2 years. We also find only small marginal gains by screening every two instead of three years. The most important objective of a screening program should be to encourage first-time screening attendance.

Evidence of a species-differentiated regulatory domain within the N-terminal region of skeletal muscle AMP deaminase.

Rabbit skeletal muscle AMP deaminase was submitted to limited proteolysis by trypsin that converts the native 80 kDa enzyme subunit to a stable product of approx. 70 kDa, which, in contrast to the native enzyme, is not sensitive to regulation by ATP at pH 6.5. Tryptic peptide mapping indicates that proteolysis is confined to the N-terminal region of the molecule, identifying in this region of AMP deaminase a non-catalytic, 95 residue regulatory domain that stabilises the binding of ATP to a distant site in the molecule. Protein sequence analysis reveals a marked degree of divergence between rat and rabbit skeletal muscle AMP deaminases in the regions containing residues 7-12 and 51-52, giving molecular basis to the hypothesis of the existence of isoenzymes of AMP deaminase in the mature skeletal muscle of the mammals.

The partial amino acid sequence of the NAD(+)-dependent glutamate dehydrogenase of Clostridium symbiosum: implications for the evolution and structural basis of coenzyme specificity.

The amino acid sequence is reported for CNBr and tryptic peptide fragments of the NAD(+)-dependent glutamate dehydrogenase of Clostridium symbiosum. Together with the N-terminal sequence, these make up about 75% of the total sequence. The sequence shows extensive similarity with that of the NADP(+)-dependent glutamate dehydrogenase of Escherichia coli (52% identical residues out of the 332 compared) allowing confident placing of the peptide fragments within the overall sequence. This demonstrated sequence similarity with the E. coli enzyme, despite different coenzyme specificity, is much greater than the similarity (31% identities) between the GDH's of C. symbiosum and Peptostreptococcus asaccharolyticus, both NAD(+)-linked. The evolutionary implications are discussed. In the 'fingerprint' region of the nucleotide binding fold the sequence Gly X Gly X X Ala is found, rather than Gly X Gly X X Gly. The sequence found here has previously been associated with NADP+ specificity and its finding in a strictly NAD(+)-dependent enzyme requires closer examination of the function of this structural motif.

Spatial and management factors associated with exposure of smallholder dairy cattle in Tanzania to tick-borne pathogens.

A cross-sectional study of serum antibody responses of cattle to tick-borne pathogens (Theileria parva, Theileria mutans,Anaplasma marginale, Babesia bigemina and Babesia bovis) was conducted on smallholder dairy farms in Tanga and Iringa Regions of Tanzania. Seroprevalence was highest for T. parva (48% in Iringa and 23% in Tanga) and B. bigemina (43% in Iringa and 27% in Tanga) and lowest for B. bovis (12% in Iringa and 6% in Tanga). We use spatial and non-spatial models, fitted using classical and Bayesian methods, to explore risk factors associated with seroprevalence. These include both fixed effects (age, grazing history and breeding status) and random effects (farm and local spatial effects). In both regions, seroprevalence for all tick-borne pathogens increased significantly with age. Animals pasture grazed in the 3 months prior to the start of the sampling period were significantly more likely to be seropositive for Theileria spp. and Babesia spp. Pasture grazed animals were more likely to be seropositive than zero-grazed animals for A. marginale, but the relationship was weaker than that observed for the other four pathogens. This study did not detect any significant differences in seroprevalence associated with other management-related variables, including the method or frequency of acaricide application. After adjusting for age, there was weak evidence of localised (<5 km) spatial correlation in exposure to some of the tick borne diseases. However, this was small compared with the 'farm-effect', suggesting that risk factors specific to the farm were more important than those common to the local neighbourhood. Many animals were seropositive for more than one pathogen and the correlation between exposure to the different pathogens remained after adjusting for the identified risk factors. Identifying the determinants of exposure to multiple tick-borne pathogens and characterizing local variation in risk will assist in the development of more effective control strategies for smallholder dairy farms.

Exacerbation of chronic obstructive pulmonary disease due to hyperinfection with Strongyloides stercoralis.

Pulmonary infection due to the filariform larvae of Strongloides stercoralis may occur in immunocompromised patients residing in endemic areas of the United States. Such infection usually presents as dyspnea with a cough that sometimes results in bloody sputum. Although the chest roentgenogram often reveals a patchy bilateral alveolar infiltrate, acute respiratory distress is unusual. We report a patient who experienced severe exacerbation of his underlying obstructive lung disease that was associated with chest infiltrates and recovery of S stercoralis from his sputum. Although initial improvement was accomplished with Thiobendazole treatment, a re-exacerbation occurred when antiparasitic therapy was completed. The persistence of his infection is correlated to factors that are commonly employed in the treatment of COPD but may be overlooked as predisposing causes of hyperinfection with S stercoralis.

Sources of variation in the ampicillin-resistant Escherichia coli concentration in the feces of organic broiler chickens.

Currently, there are limited published data for the population dynamics of antimicrobial-resistant commensal bacteria. This study was designed to evaluate both the proportions of the Escherichia coli populations that are resistant to ampicillin at the level of the individual chicken on commercial broiler farms and the feasibility of obtaining repeated measures of fecal E. coli concentrations. Short-term temporal variation in the concentration of fecal E. coli was investigated, and a preliminary assessment was made of potential factors involved in the shedding of high numbers of ampicillin-resistant E. coli by growing birds in the absence of the use of antimicrobial drugs. Multilevel linear regression modeling revealed that the largest component of random variation in log-transformed fecal E. coli concentrations was seen between sampling occasions for individual birds. The incorporation of fixed effects into the model demonstrated that the older, heavier birds in the study were significantly more likely (P = 0.0003) to shed higher numbers of ampicillin-resistant E. coli. This association between increasing weight and high shedding was not seen for the total fecal E. coli population (P = 0.71). This implies that, in the absence of the administration of antimicrobial drugs, the proportion of fecal E. coli that was resistant to ampicillin increased as the birds grew. This study has shown that it is possible to collect quantitative microbiological data on broiler farms and that such data could make valuable contributions to risk assessments concerning the transfer of resistant bacteria between animal and human populations.