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Clinical features associated with an increased risk of thyroid malignancy in patients with follicular neoplasia by fine-needle aspiration.

The application of fine-needle aspiration (FNA) to the evaluation of the thyroid nodule has greatly enhanced the ability of the clinician to appropriately select patients for thyroidectomy. However, despite extensive experience with thyroid FNA, the cytological distinction of benign from malignant follicular neoplasia remains problematic. As a result, most patients with FNA findings of a follicular neoplasm are referred for thyroidectomy. The goal of the present study was to develop clinical criteria capable of predicting malignancy in patients with an FNA diagnosis of follicular neoplasm. Among 1121 patients undergoing thyroid FNA at two large teaching centers during the period 1990 to 1995, 149 patients had cytological findings consistent with a follicular neoplasm. Among 103 patients referred for thyroidectomy, 22 (21%) were found to have a malignancy in the biopsied nodule. Among patients subjected to thyroidectomy, the risk of malignancy was significantly higher when follicular neoplasia was present in a male (43% vs. 16% for females, p = 0.007), when the nodule was greater than 4 cm to palpation (40% vs. 13% for nodules less than 4 cm, p = 0.03), or when the nodule was judged to be solitary by palpation (25% vs. 6% for a dominant nodule in a multinodular goiter, p = 0.02). Bayesian analysis of the data reveals that after an FNA showing a follicular neoplasm, the risk of malignancy in males with large nodules was nearly 80%, compared with a rate of only 3% in females with small nodules. These results suggest that clinical features including gender, nodule size, and character of the gland by palpation can be systematically integrated into the decision analysis, thereby improving the selection of patients for surgical referral.

Bayes Theorem↗

Association of physical activity with development of uterine leiomyoma.

The relation between physical activity and uterine leiomyomata (fibroids) has received little study, but exercise is protective for breast cancer, another hormonally mediated tumor. Participants in this study were randomly selected members of a health plan based in Washington, DC, aged 35-49 years (734 African Americans, 455 Whites) enrolled between 1996 and 1999. Fibroid status was based on ultrasound screening. Physical activity was based on detailed interview questions. Logistic regression with adjustment for body mass index and other risk factors showed that women in the highest category of physical activity were significantly less likely to have fibroids (odds ratio = 0.6, 95% confidence interval = 0.4, 0.9 for the highest vs. the lowest category (equivalent to approximately > or =7 hours/week vs <2 hours/week)). There was a dose-response pattern; a significant trend was seen for both African-American and White women. A multistate Bayesian analysis indicated that exercise was associated with tumor onset more strongly than with tumor growth. When data for women who reported major fibroid-related symptoms were excluded, results remained essentially unchanged, suggesting that the observed association could not be attributed to reverse causation (fibroids preventing exercise). The authors concluded that regular exercise might help women prevent fibroids.

Adolescent↗

Alteration of vancomycin pharmacokinetics during cardiopulmonary bypass in patients undergoing cardiac surgery.

The alteration of vancomycin pharmacokinetics during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery was studied. Eighteen patients were enrolled in the study. Vancomycin (1 g) was intravenously infused one to two hours before surgery. Blood samples were taken before, during, and after CPB. Serum drug concentrations were determined by an automated fluorescence polarization immunoassay and adjusted, with a bayesian analysis, to a bi-compartmental model implemented in a pharmacokinetic system program. Serum creatinine, hematocrit, and plasma proteins were also measured before, during, and after CPB. During CPB, serum creatinine, hematocrit, and plasma protein values all decreased significantly (p < 0.05). Serum vancomycin concentration also diminished abruptly with CPB (7.04 micrograms/mL; 95% confidence interval, 5.70-8.38 micrograms/mL) but increased moderately during the next 30 minutes, probably attributable to redistribution into plasma from tissue stores. Vancomycin's apparent volume of distribution showed an important increase during CPB (58.8%) (p < 0.0005), and its systemic clearance also increased significantly after CPB (19.7%) (p < 0.0005). The decrease in serum vancomycin concentration seems mediated by the hemodilution associated with the pump prime volume. Vancomycin's mean +/- S.D. nadir serum concentration before the next dose was 7.13 +/- 2.1 micrograms/mL. In patients undergoing cardiac surgery and treated prophylactically with a 1-g preoperative i.v. dose of vancomycin, the onset of CPB was associated with a drop in serum vancomycin concentration.

Adult↗

Pharmacokinetics of low-dose carboplatin and applicability of a method of calculation for estimating individual drug clearance.

BACKGROUND: Carboplatin is the only cancer drug for which conventional doses are individually adjusted according to estimated clearance and target area under the curve (AUC). The aim of this prospective study was (i) to evaluate intra- and interpatient variability of ultrafilterable (UF) carboplatin AUC(0-)(infinity) and (ii) to test whether the prediction of carboplatin clearance according to the Chatelut formula established for conventional carboplatin doses was accurate for low carboplatin doses. MATERIALS AND METHODS: Thirty-one head and neck cancer patients (29 men, two women, mean age 55.9 years) received concomitant radiotherapy (Rgamma 2 Gy/day) and chemotherapy (carboplatin 50 mg/m(2)/day i.v.) for 7 weeks: Rgamma was administered 5 days/week (days 1-5) and carboplatin 2 days/week (days 1 and 4). Pharmacokinetics was performed once per week. A limited sample strategy based on Bayesian analysis was first validated and blood was subsequently taken 1 and 4 h after the end of carboplatin administration. RESULTS: A total of 143 cycles was analyzed. Ultrafilterable carboplatin AUC(0-)(infinity) ranged from 0.360 to 4.200 mg.min/ml (mean 0.830, median 0.670). As a corollary, UF carboplatin clearance ranged from 19.1 to 244.7 ml/min. Ultrafilterable carboplatin concentrations were very stable over time: AUC(0-)(infinity) variability due to treatment duration contributed to <1% of the total variance, while interpatient variability contributed to 68.6%. Accordingly, intrasubject effect was not significant (P = 0.38) whereas intersubject effect was highly significant (P <0.001). These results suggest that optimal dosage for targeting a given AUC may vary within a 13-fold range between patients. The Chatelut formula, based on creatininemia, body weight, age and sex, over estimates carboplatin clearance by 40% on average (bias 95% CI 29.6% to 51.1%). No significant relationship was observed between either bone marrow toxicity or creatinine clearance decrease and carboplatin pharmacokinetics. CONCLUSIONS: The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m(2)) is not applicable for targeting low AUC (<1 mg x min/ml).

Adult↗

A Bayesian method for analysing spotted microarray data.

In the decade since their invention, spotted microarrays have been undergoing technical advances that have increased the utility, scope and precision of their ability to measure gene expression. At the same time, more researchers are taking advantage of the fundamentally quantitative nature of these tools with refined experimental designs and sophisticated statistical analyses. These new approaches utilise the power of microarrays to estimate differences in gene expression levels, rather than just categorising genes as up- or down-regulated, and allow the comparison of expression data across multiple samples. In this review, some of the technical aspects of spotted microarrays that can affect statistical inference are highlighted, and a discussion is provided of how several methods for estimating gene expression level across multiple samples deal with these challenges. The focus is on a Bayesian analysis method, BAGEL, which is easy to implement and produces easily interpreted results.

Algorithms↗

Predicting gene regulation by sigma factors in Bacillus subtilis from genome-wide data.

MOTIVATION: Sigma factors regulate the expression of genes in Bacillus subtilis at the transcriptional level. We assess the accuracy of a fold-change analysis, Bayesian networks, dynamic models and supervised learning based on coregulation in predicting gene regulation by sigma factors from gene expression data. To improve the prediction accuracy, we combine sequence information with expression data by adding their log-likelihood scores and by using a logistic regression model. We use the resulting score function to discover currently unknown gene regulations by sigma factors. RESULTS: The coregulation-based supervised learning method gave the most accurate prediction of sigma factors from expression data. We found that the logistic regression model effectively combines expression data with sequence information. In a genome-wide search, highly significant logistic regression scores were found for several genes whose transcriptional regulation is currently unknown. We provide the corresponding RNA polymerase binding sites to enable a straightforward experimental verification of these predictions.

Algorithms↗

ParIS Genome Rearrangement server.

SUMMARY: ParIS Genome Rearrangement is a web server for a Bayesian analysis of unichromosomal genome pairs. The underlying model allows inversions, transpositions and inverted transpositions. The server generates a Markov chain using a Partial Importance Sampler technique, and samples trajectories of mutations from this chain. The user can specify several marginalizations to the posterior: the posterior distribution of number of mutations needed to transform one genome into another, length distribution of mutations, number of mutations that have occurred at a given site. Both text and graphical outputs are available. We provide a limited server, a downloadable unlimited server that can be installed locally on any linux/Unix operating system, and a database of mitochondrial gene orders.

Algorithms↗

LAMARC 2.0: maximum likelihood and Bayesian estimation of population parameters.

UNLABELLED: We present a Markov chain Monte Carlo coalescent genealogy sampler, LAMARC 2.0, which estimates population genetic parameters from genetic data. LAMARC can co-estimate subpopulation Theta = 4N(e)mu, immigration rates, subpopulation exponential growth rates and overall recombination rate, or a user-specified subset of these parameters. It can perform either maximum-likelihood or Bayesian analysis, and accomodates nucleotide sequence, SNP, microsatellite or elecrophoretic data, with resolved or unresolved haplotypes. It is available as portable source code and executables for all three major platforms. AVAILABILITY: LAMARC 2.0 is freely available at http://evolution.gs.washington.edu/lamarc

Bayes Theorem↗

Point-source modelling using matched case-control data.

We describe an extension to matched case-control studies of the parametric modelling framework developed by Diggle (1990) and Diggle and Rowlingson (1994) to investigate raised risk around putative sources of environmental pollution. We use a conditional likelihood approach for the family of risk functions considered in Diggle and Rowlingson (1994). We show that the likelihood surface that results from these models may be highly irregular, and provide a Bayesian analysis in which we investigate the posterior distribution using Markov chain Monte Carlo. An analysis of one-one matched data that were collected to investigate the relationship between respiratory disease and distance to roads in East London is presented.

Journal Article↗

Impact of nonignorable coarsening on Bayesian inference.

The coarse data model of Heitjan and Rubin (1991) generalizes the missing data model of Rubin (1976) to cover other forms of incompleteness such as censoring and grouping. The model has 2 components: an ideal data model describing the distribution of the quantity of interest and a coarsening mechanism that describes a distribution over degrees of coarsening given the ideal data. The coarsening mechanism is said to be nonignorable when the degree of coarsening depends on an incompletely observed ideal outcome, in which case failure to properly account for it can spoil inferences. A theme in recent research is to measure sensitivity to nonignorability by evaluating the effect of a small departure from ignorability on the maximum likelihood estimate (MLE) of a parameter of the ideal data model. One such construct is the "index of local sensitivity to nonignorability" (ISNI) (Troxel and others, 2004), which is the derivative of the MLE with respect to a nonignorability parameter evaluated at the ignorable model. In this paper, we adapt ISNI to Bayesian modeling by instead defining it as the derivative of the posterior expectation. We propose the application of ISNI as a first step in judging the robustness of a Bayesian analysis to nonignorable coarsening. We derive formulas for a range of models and apply the method to evaluate sensitivity to nonignorable coarsening in 2 real data examples, one involving missing CD4 counts in an HIV trial and the other involving potentially informatively censored relapse times in a leukemia trial.

Bayes Theorem↗

Optimal pharmacological stress testing for the diagnosis of coronary artery disease: a probabilistic approach.

Previous reports have suggested that dobutamine stress echocardiography compares favourably with other stress agent-imaging modality combinations for the detection of coronary artery disease. However, in daily clinical practice the value of a test is defined on a probability basis. To study the relative diagnostic contribution of clinical and dobutamine stress test variables, Bayesian analysis was performed in 223 patients with suspected coronary artery disease, who underwent coronary angiography and a high-dose dobutamine stress test in conjunction with electrocardiography, echocardiography and Technetium-99m sestamibi SPECT myocardial perfusion scintigraphy. According to the pre-test (clinical) probabilities, patients were divided into low-, intermediate- and high-risk groups; 155 patients were in the intermediate-risk group. After dobutamine stress echocardiography the number of patients in this intermediate-risk group was reduced to 102 (P < 0.0001). This reduction of patients in the intermediate-risk group by echocardiography was better than perfusion scintigraphy (102 vs 126 patients, P < 0.05) or classic markers of ischaemia such as angina and/or ST-segment changes (102 vs 150, P < 0.0001). Moreover, there was a good correlation between the echocardiographic post-test probabilities and the true distribution of coronary artery disease.

Aged↗

Y chromosomal evidence for the origins of oceanic-speaking peoples.

A number of alternative hypotheses seek to explain the origins of the three groups of Pacific populations-Melanesians, Micronesians, and Polynesians-who speak languages belonging to the Oceanic subfamily of Austronesian languages. To test these various hypotheses at the genetic level, we assayed diversity within the nonrecombining portion of the Y chromosome, which contains within it a relatively simple record of the human past and represents the most informative haplotypic system in the human genome. High-resolution haplotypes combining binary, microsatellite, and minisatellite markers were generated for 390 Y chromosomes from 17 Austronesian-speaking populations in southeast Asia and the Pacific. Nineteen paternal lineages were defined and a Bayesian analysis of coalescent simulations was performed upon the microsatellite diversity within lineages to provide a temporal aspect to their geographical distribution. The ages and distributions of these lineages provide little support for the dominant archeo-linguistic model of the origins of Oceanic populations that suggests that these peoples represent the Eastern fringe of an agriculturally driven expansion initiated in southeast China and Taiwan. Rather, most Micronesian and Polynesian Y chromosomes appear to originate from different source populations within Melanesia and Eastern Indonesia. The Polynesian outlier, Kapingamarangi, is demonstrated to be an admixed Micronesian/Polynesian population. Furthermore, it is demonstrated that a geographical rather than linguistic classification of Oceanic populations best accounts for their extant Y chromosomal diversity.

Emigration and Immigration↗

Selection on rapidly evolving proteins in the Arabidopsis genome.

Genes that have undergone positive or diversifying selection are likely to be associated with adaptive divergence between species. One indicator of adaptive selection at the molecular level is an excess of amino acid replacement fixed differences per replacement site relative to the number of synonymous fixed differences per synonymous site (omega = K(a)/K(s)). We used an evolutionary expressed sequence tag (EST) approach to estimate the distribution of omega among 304 orthologous loci between Arabidopsis thaliana and A. lyrata to identify genes potentially involved in the adaptive divergence between these two Brassicaceae species. We find that 14 of 304 genes (approximately 5%) have an estimated omega > 1 and are candidates for genes with increased selection intensities. Molecular population genetic analyses of 6 of these rapidly evolving protein loci indicate that, despite their high levels of between-species nonsynonymous divergence, these genes do not have elevated levels of intraspecific replacement polymorphisms compared to previously studied genes. A hierarchical Bayesian analysis of protein-coding region evolution within and between species also indicates that the selection intensities of these genes are elevated compared to previously studied A. thaliana nuclear loci.

Arabidopsis↗

Estimating the parameters of a model for protein-protein interaction graphs.

We find accurate approximations for the expected number of three-cycles and unchorded four-cycles under a stochastic distribution for graphs that has been proposed for modelling yeast two-hybrid protein-protein interaction networks. We show that unchorded four-cycles are characteristic motifs under this model and that the count of unchorded four-cycles in the graph is a reliable statistic on which to base parameter estimation. Finally, we test our model against a range of experimental data, obtain parameter estimates from these data and investigate possible improvements in the model. Characterization of this model lays the foundation for its use as a prior distribution in a Bayesian analysis of yeast two-hybrid networks that can potentially aid in identifying false-positive and false-negative results.

Algorithms↗

Time dependency of molecular rate estimates and systematic overestimation of recent divergence times.

Studies of molecular evolutionary rates have yielded a wide range of rate estimates for various genes and taxa. Recent studies based on population-level and pedigree data have produced remarkably high estimates of mutation rate, which strongly contrast with substitution rates inferred in phylogenetic (species-level) studies. Using Bayesian analysis with a relaxed-clock model, we estimated rates for three groups of mitochondrial data: avian protein-coding genes, primate protein-coding genes, and primate d-loop sequences. In all three cases, we found a measurable transition between the high, short-term (< 1-2 Myr) mutation rate and the low, long-term substitution rate. The relationship between the age of the calibration and the rate of change can be described by a vertically translated exponential decay curve, which may be used for correcting molecular date estimates. The phylogenetic substitution rates in mitochondria are approximately 0.5% per million years for avian protein-coding sequences and 1.5% per million years for primate protein-coding and d-loop sequences. Further analyses showed that purifying selection offers the most convincing explanation for the observed relationship between the estimated rate and the depth of the calibration. We rule out the possibility that it is a spurious result arising from sequence errors, and find it unlikely that the apparent decline in rates over time is caused by mutational saturation. Using a rate curve estimated from the d-loop data, several dates for last common ancestors were calculated: modern humans and Neandertals (354 ka; 222-705 ka), Neandertals (108 ka; 70-156 ka), and modern humans (76 ka; 47-110 ka). If the rate curve for a particular taxonomic group can be accurately estimated, it can be a useful tool for correcting divergence date estimates by taking the rate decay into account. Our results show that it is invalid to extrapolate molecular rates of change across different evolutionary timescales, which has important consequences for studies of populations, domestication, conservation genetics, and human evolution.

Animals↗

The phylogenetic positions of three Basal-hexapod groups (protura, diplura, and collembola) based on ribosomal RNA gene sequences.

This study combined complete 18S with partial 28S ribosomal RNA gene sequences ( approximately 2,000 nt in total) to investigate the relations of basal hexapods. Ten species of Protura, 12 of Diplura, and 10 of Collembola (representing all subgroups of these three clades) were sequenced, along with 5 true insects and 8 other arthropods, which served as out-groups. Trees were constructed with maximum parsimony, maximum likelihood, Bayesian analysis, and minimum-evolution analysis of LogDet-transformed distances. All methods yielded strong support for a clade of Protura plus Diplura, here named Nonoculata, and for monophyly of the Diplura. Parametric-bootstrapping analysis showed our data to be inconsistent with previous hypotheses (P < 0.01) that joined Protura with Collembola (Ellipura), that said Diplura are sister to true insects or are diphyletic, and that said Collembola are not hexapods. That is, our data are consistent with hexapod monophyly and Collembola grouped weakly with "Protura + Diplura" under most analytical conditions. As a caveat to the above conclusions, the sequences showed nonstationarity of nucleotide frequencies across taxa, so the CG-rich sequences of the diplurans and proturans may have grouped together artifactually; however, the fact that the LogDet method supported this group lessens this possibility. Within the basal hexapod groups, where nucleotide frequencies were stationary, traditional taxonomic subgroups generally were recovered: i.e., within Protura, the Eosentomata and Acerentomata (but Sinentomata was not monophyletic); within Collembola, the Arthropleona, Poduromorpha, and Entomobryomorpha (but Symphypleona was polyphyletic); and in Diplura, the most complete data set (> 2,100 nt) showed monophyly of Campodeoidea and of Japygoidea, and most methods united Projapygoidea with Japygoidea.

Animals↗

Early penguin fossils, plus mitochondrial genomes, calibrate avian evolution.

Testing models of macroevolution, and especially the sufficiency of microevolutionary processes, requires good collaboration between molecular biologists and paleontologists. We report such a test for events around the Late Cretaceous by describing the earliest penguin fossils, analyzing complete mitochondrial genomes from an albatross, a petrel, and a loon, and describe the gradual decline of pterosaurs at the same time modern birds radiate. The penguin fossils comprise four naturally associated skeletons from the New Zealand Waipara Greensand, a Paleocene (early Tertiary) formation just above a well-known Cretaceous/Tertiary boundary site. The fossils, in a new genus (Waimanu), provide a lower estimate of 61-62 Ma for the divergence between penguins and other birds and thus establish a reliable calibration point for avian evolution. Combining fossil calibration points, DNA sequences, maximum likelihood, and Bayesian analysis, the penguin calibrations imply a radiation of modern (crown group) birds in the Late Cretaceous. This includes a conservative estimate that modern sea and shorebird lineages diverged at least by the Late Cretaceous about 74 +/- 3 Ma (Campanian). It is clear that modern birds from at least the latest Cretaceous lived at the same time as archaic birds including Hesperornis, Ichthyornis, and the diverse Enantiornithiformes. Pterosaurs, which also coexisted with early crown birds, show notable changes through the Late Cretaceous. There was a decrease in taxonomic diversity, and small- to medium-sized species disappeared well before the end of the Cretaceous. A simple reading of the fossil record might suggest competitive interactions with birds, but much more needs to be understood about pterosaur life histories. Additional fossils and molecular data are still required to help understand the role of biotic interactions in the evolution of Late Cretaceous birds and thus to test that the mechanisms of microevolution are sufficient to explain macroevolution.

Animals↗

Prediction of carcinogenic potency by short-term genotoxicity tests.

Past attempts to correlate carcinogenic potencies of chemicals with potencies in causing mutations or other endpoints in short-term genotoxicity tests have found quantitative correlations to be weak except for restricted classes of chemicals. We have classified 379 chemicals on the basis of the rodent carcinogenic potencies calculated by Gold and co-workers as strong carcinogens, moderate carcinogens, weak carcinogens, or non-carcinogens, and have compared the qualitative results of short-term tests (positive or negative) for each of the four classes of chemicals. For most of the short-term tests analyzed, the proportion of positive results increased with carcinogenic potency, being highest for strong carcinogens, lower for moderate carcinogens, lower still for weak carcinogens, and least for non-carcinogens. This differential sensitivity based on carcinogenic potency implies that short-term test responses could be used to predict the carcinogenic potency of unknown chemicals. We have quantified these predictions using Bayesian analysis so that positive or negative results in short-term tests can be interpreted as predicting that a chemical may be a strong carcinogen, a moderate carcinogen, a weak carcinogen, or a non-carcinogen. Possible screening strategies based on these predictions are discussed.

Animals↗