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PubMedDate not supplied

Large-sample Bayesian posterior distributions for probabilistic sensitivity analysis.

In probabilistic sensitivity analyses, analysts assign probability distributions to uncertain model parameters and use Monte Carlo simulation to estimate the sensitivity of model results to parameter uncertainty. The authors present Bayesian methods for constructing large-sample approximate posterior distributions for probabilities, rates, and relative effect parameters, for both controlled and uncontrolled studies, and discuss how to use these posterior distributions in a probabilistic sensitivity analysis. These results draw on and extend procedures from the literature on large-sample Bayesian posterior distributions and Bayesian random effects meta-analysis. They improve on standard approaches to probabilistic sensitivity analysis by allowing a proper accounting for heterogeneity across studies as well as dependence between control and treatment parameters, while still being simple enough to be carried out on a spreadsheet. The authors apply these methods to conduct a probabilistic sensitivity analysis for a recently published analysis of zidovudine prophylaxis following rapid HIV testing in labor to prevent vertical HIV transmission in pregnant women.

Bayes Theorem↗

PubMed2004

Bayesian hierarchical error model for analysis of gene expression data.

MOTIVATION: Analysis of genome-wide microarray data requires the estimation of a large number of genetic parameters for individual genes and their interaction expression patterns under multiple biological conditions. The sources of microarray error variability comprises various biological and experimental factors, such as biological and individual replication, sample preparation, hybridization and image processing. Moreover, the same gene often shows quite heterogeneous error variability under different biological and experimental conditions, which must be estimated separately for evaluating the statistical significance of differential expression patterns. Widely used linear modeling approaches are limited because they do not allow simultaneous modeling and inference on the large number of these genetic parameters and heterogeneous error components on different genes, different biological and experimental conditions, and varying intensity ranges in microarray data. RESULTS: We propose a Bayesian hierarchical error model (HEM) to overcome the above restrictions. HEM accounts for heterogeneous error variability in an oligonucleotide microarray experiment. The error variability is decomposed into two components (experimental and biological errors) when both biological and experimental replicates are available. Our HEM inference is based on Markov chain Monte Carlo to estimate a large number of parameters from a single-likelihood function for all genes. An F-like summary statistic is proposed to identify differentially expressed genes under multiple conditions based on the HEM estimation. The performance of HEM and its F-like statistic was examined with simulated data and two published microarray datasets-primate brain data and mouse B-cell development data. HEM was also compared with ANOVA using simulated data. AVAILABILITY: The software for the HEM is available from the authors upon request.

Algorithms↗

PubMed2004

Population genetic structure of and inbreeding in an insular cattle breed, the Jersey, and its implications for genetic resource management.

The Jersey is a ubiquitous and successful breed of cattle that originates from the UK Channel Island of Jersey. While the breed has been exported extensively, no imports have taken place to the island since 1789, leading to a concern regarding possible losses of genetic diversity and increased inbreeding. We have conducted the first large-scale genetic analysis of the Jersey cattle using only samples from the island. A total of 223 cattle from all parishes except one were genotyped for 12 microsatellite loci. The average number of alleles per locus and expected heterozygosity were found to be comparatively high (n(A)=4, H(e)=0.64) with respect to that observed in a number of continental breeds. Only breeds that have been upgraded and are therefore the result of admixture are clearly more variable than the Jersey. We also found a significant but limited amount of genetic differentiation between parishes (F(st)=0.013), or even between farms (F(st)=0.035) despite an apparent lack of movement. This is confirmed by the application of two recent statistical methods. A Bayesian partition analysis shows that the most probable value of K, the number of possible hidden partitions, is 1 (P approximately 0.98). K=2 has a much lower probability (P approximately 0.02) while other values are essentially zero. Similarly, we were able to show that there was no support for departure from panmixia other than due to population structure, and thus that there is sufficient background gene flow across the island to overcome local drift. Overall, it appears that the current level of genetic diversity and its distribution within the island means it is unnecessary to import unrelated genetic material to the island for management purposes.

Alleles↗

PubMed2003

Molecular phylogenetic analyses indicate that the Ixodes ricinus complex is a paraphyletic group.

The Ixodes ricinus species complex is a group of ticks distributed in almost all geographic regions of the world. Lyme borreliosis spirochetes are primarily transmitted by tick species within this complex. It has been hypothesized that the Lyme vector ticks around the world are closely related and represent a monophyletic group. This implies that vector competence in ixodid ticks for Lyme agents might have evolved only once. To test this hypothesis, we used a molecular phylogenetic approach. Two fragments of mitochondrial 16S ribosomal deoxyribonucleic acid were sequenced from 11 species in the I. ricinus complex and from 16 other species of Ixodes. Phylogenetic analysis using Bayesian methodology indicated that the I. ricinus complex is not a monophyletic group unless 3 additional Ixodes species are included in it. The known major vectors of Lyme disease agents in different areas of the world are not sister taxa. This suggests that acquisition of the ability to transmit borreliosis agents in species of Ixodes may have multiple origins.

Animals↗

PubMed2006

Psychological distress among adolescents, and its relationship to individual, family and area characteristics in East London.

This paper identifies factors associated with variation in psychosocial distress among adolescents in a relatively deprived and ethnically diverse inner city setting in London, UK. The research draws on literature which discusses whether neighbourhood socio-economic conditions are associated with mental health, as well as attributes of individual adolescents and their families. We report an analysis of data from the Research with East London Adolescents: Community Health Survey (RELACHS). The survey collected data on mental health measured by the Strengths and Difficulties Questionnaire (SDQ), and on various aspects of individual and family circumstances. These data were linked with information about social and economic conditions in 'middle layer standard output areas' (MSOA) used for the population Census 2001, having a mean total population of 6767 in the study area. Census statistics including the Indices of Deprivation for 2004 proposed by the Office of the Deputy Prime Minister, were used to describe the socio-economic conditions within these areas. Although the socio-economic disparities among small areas were not typical of those across the whole of the country, there were differences in levels of deprivation and crime, social fragmentation, and ethnic composition. A Bayesian regression analysis using Gibbs sampling in the programme WinBugs investigated whether there was variability in SDQ at both individual and area (MSOA) level, and whether the predictor variables at both levels were significantly associated with SDQ. Individuals from Asian or Black ethnic groups, and those in families with harmonious relationships and no financial stress had significantly lower SDQ scores, i.e. better health. Those who had special educational needs or long standing illness, or were from reconstituted families had significantly worse SDQ scores. About 6% of the variation in SDQ was associated with area differences. However, this area variation was not related to differences in area indicators of socio-economic deprivation, crime or social fragmentation. There was a complex association between SDQ and ethnic composition of neighbourhoods.

Adolescent↗

PubMed2004

Bayesian pharmacokinetics of gentamicin in a haemodialysis population.

BACKGROUND: Aminoglycosides are commonly used in the haemodialysis population. Standard pharmacokinetic approaches require multiple sampling to describe the parameters of drug distribution and elimination in the intra- and interdialytic periods. OBJECTIVE: To characterise the pharmacokinetics of gentamicin in a haemodialysis population by using Bayesian pharmacokinetic methods and only two plasma concentrations. DESIGN AND PARTICIPANTS: Prospective case series of 13 adult (aged 36-70 years) haemodialysis patients (Fresenius F80 dialysers were used) receiving gentamicin. METHODS: Patients with suspected or confirmed Gram-negative infections were given gentamicin. At 48 hours after receiving the dose (at the next haemodialysis session), patients provided two blood samples, one immediately before the dialysis session and another 1 hour after haemodialysis. Data on dosage, timing and plasma concentrations for all subjects were analysed with PASTRX version 10.6 and Bayesian pharmacokinetic analysis. Volume of distribution (Vd), interdialytic elimination rate constant (k(inter)), interdialytic elimination half-life (t1/2beta, inter)) and interdialytic clearance (CL(inter)) were determined from a single predialysis plasma concentration. Elimination rate constant (k(dial)), elimination half-life (t1/2beta, dial)) and clearance (CL(dial)) during 3.5-4 hours of dialysis were also determined from the pre- and post-plasma concentrations. RESULTS: Pharmacokinetic parameters (mean +/- SD) were: Vd 0.288 +/- 0.002 L/kg, k(inter) 0.015 +/- 0.004h(-1), t1/2beta, inter) 48 +/- 11h, CL(inter) 5.9 +/- 2.4 mL/min, k(dial) 0.25 +/- 0.05 h(-1), t1/2beta, dial) 3.0 +/- 1.0h and CL(dial) 91 +/- 24 mL/min. CONCLUSIONS: The rate of elimination of gentamicin was 17-fold greater (95% CI 13.7-20.7) on haemodialysis with a Fresenius F80 than off haemodialysis. All of the pharmacokinetic parameters of interest were determined using Bayesian pharmacokinetic procedures and only two plasma gentamicin concentrations.

Adult↗

PubMed2002

[Bayesian thinking on its way into medical statistics?].

BACKGROUND: Bayesian statistical analysis is a paradigm quite different from traditional statistical inference. We wanted to show the usefulness of this approach for some medical problems. MATERIALS AND METHODS: We started with Bayes equation as it is used for estimating the probability of illness based on a specific laboratory test. We also looked into a recent Cochrane report on mammography that accepted two studies as valid and five others as biased. In comparison we used examples of clinical trials from other areas that have been misinterpreted by the use of a traditional statistical approach only. RESULTS: We found that by taking into account our prior beliefs about the likely effects on breast cancer mortality of routine radiological screening programmes, the new data fit well into an estimate of a 5% mortality reduction with a 77% chance that there is a positive effect of screening. INTERPRETATION: Bayesian statistics is helpful in making decisions on the basis of experimental evidence by taking into account our prior knowledge, whereas p-values in traditional statistics only give information on how often we will end up with a false positive conclusion in the long run.

Bayes Theorem↗

PubMed2004

On the origins of medfly invasion and expansion in Australia.

As a result of their rapid expansion and large larval host range, true fruit flies are among the world's most important agricultural pest species. Among them, Ceratitis capitata has become a model organism for studies on colonization and invasion processes. The genetic aspects of the medfly invasion process have already been analysed throughout its range, with the exception of Australia. Bioinvasion into Australia is an old event: medfly were first captured in Australia in 1895, near Perth. After briefly appearing in Tasmania and the eastern states of mainland Australia, medfly had disappeared from these areas by the 1940s. Currently, they are confined to the western coastal region. South Australia seems to be protected from medfly infestations both by the presence of an inhospitable barrier separating it from the west and by the limited number of transport routes. However, numerous medfly outbreaks have occurred since 1946, mainly near Adelaide. Allele frequency data at 10 simple sequence repeat loci were used to study the genetic structure of Australian medflies, to infer the historical pattern of invasion and the origin of the recent outbreaks. The combination of phylogeographical analysis and Bayesian tests showed that colonization of Australia was a secondary colonization event from the Mediterranean basin and that Australian medflies were unlikely to be the source for the initial Hawaiian invasion. Within Australia, the Perth area acted as the core range and was the source for medfly bioinvasion in both Western and South Australia. Incipient differentiation, as a result of habitat fragmentation, was detected in some localized areas at the periphery of the core range.

Animals↗

PubMed2002

Efficacy of prophylactic antibiotic therapy in spinal surgery: a meta-analysis.

OBJECTIVE: There is considerable variation in practice regarding the use of prophylactic antibiotic therapy in spinal operations. To date, individual studies have not demonstrated a significant benefit for prophylactic antibiotic therapy in spinal operations. METHODS: Systematic database searches for randomized prospective trials of prophylactic antibiotic therapy in spinal surgery, general neurosurgery, and orthopedic surgery were performed. Random-effects meta-analysis and Bayesian meta-regressions of treatment benefits versus baseline infection rates and other trial characteristics were performed. RESULTS: Six prospective randomized trials or trial subgroups, enrolling 843 patients, were identified, i.e., one spinal surgery trial, four general neurosurgery trials, and one general orthopedic surgery trial. No individual trial demonstrated a statistically significant effect of prophylactic antibiotic therapy for spinal surgery patients. Raw pooled infection rates were 2.2% (10 of 451 patients) with antibiotics and 5.9% (23 of 392 patients) without antibiotics. Individual trial infection rates ranged from 1.2 to 8.5%. The pooled odds ratio was 0.37 (95% confidence interval, 0.17-0.78), favoring antibiotic treatment (P < 0.01). There was no significant heterogeneity in treatment efficacy among the trials. Bayesian meta-regression was used to test whether antibiotics were less effective in trials with low baseline infection rates and whether an optimal antibiotic regimen could be identified. There was no significant difference in antibiotic treatment effects in trials with lower baseline infection rates, in trials using antibiotics with gram-negative coverage in addition to gram-positive coverage, or in trials using multiple-dose versus single-dose regimens. Nonrandomized studies of antibiotic therapy in spinal surgery yielded greater treatment effect estimates than did randomized trials, but not significantly so. CONCLUSION: Prophylactic antibiotic therapy is beneficial for spinal surgery, even when expected infection rates without antibiotic treatment are low.

Antibiotic Prophylaxis↗

PubMed1998

Ability of a first-pass pharmacokinetic model to characterize cyclosporine blood concentrations after administrations of Sandimmune or Neoral formulations.

Most recent cyclosporine (CsA) pharmacokinetic (PK) studies have focused on noncompartmental analysis. Because CsA undergoes significant first-pass elimination after oral dosing, the most appropriate compartment model may need to take this process into account for the construction of a valid population PK model for Sandimmune (SAN) and Neoral (NEO) formulations. Twenty patients with cardiac transplants were stabilized for at least 4 weeks on a certain dose of SAN, then changed to the same daily dose of NEO. Blood samples were obtained at times 0, 1, 2, 3, 4, 6 and 12 hours after dosing at steady state. Pharmacokinetic modeling was performed using ADAPT II. Quality of fit was assessed by visual graph inspections, R2 values, and Akaike criterion test. Eight pharmacokinetic models were constructed and evaluated. These included one- and two-compartment with and without a first-pass effect and a time-lag. Neoral and SAN data were consistently best fitted using a two-compartment or the two-compartment first-pass model. However, a time-lag process was found to be necessary for SAN. The use of a two-compartment first-pass with (SAN) or without (NEO) a time-lag process appears to fit CsA concentrations at least as well as a two-compartment model. This first-pass model may be very useful for population pharmacokinetics and Bayesian control analysis.

Absorption↗

PubMed1996

Borrowing strength from external trials in a meta-analysis.

There exists a variety of situations in which a random effects meta-analysis might be undertaken using a small number of clinical trials. A problem associated with small meta-analyses is estimating the heterogeneity between trials. To overcome this problem, information from other related studies may be incorporated into the meta-analysis. A Bayesian approach to this problem is presented using data from previous meta-analyses in the same therapeutic area to formulate a prior distribution for the heterogeneity. The treatment difference parameters are given non-informative priors. Further, related trials which compare one or other of the treatments of interest with a common third treatment are included in the model to improve inference on both the heterogeneity and the treatment difference. Two approaches to estimating relative efficacy are considered, namely a general parametric approach and a method explicit to binary data. The methodology is illustrated using data from 26 clinical trials which investigate the prevention of cirrhosis using beta-blockers and sclerotherapy. Both sources of external information lead to more precise posterior distributions for all parameters, in particular that representing heterogeneity.

Adrenergic beta-Antagonists↗

PubMed1986

Contraception with the cervical cap: effectiveness, safety, continuity of use, and user satisfaction.

With the growing interest in barrier contraceptive methods, the cervical cap has come back into use in North America. We examined the cap's effectiveness, safety, continuity of use, and user satisfaction among 617 women who were fitted at a family planning clinic in Toronto, Canada, between May 1981 and November 1983. Follow-up information was available for 516 of these women. Using a life table analysis with Bayesian adjustment, the probability of becoming pregnant after 12 months of use was 0.166 with a standard error of 0.022. There is evidence that after 1 year of use the caps deteriorate and that this deterioration may increase the risk of pregnancy. Many of the women in this study were very satisfied with the cervical cap; however, such problems as dislodgement, discomfort to user and partner, difficulty with insertion and removal, and unpleasant odour affected acceptability and continuity of use. It is likely that these problems could be alleviated by improving the quality of or changing the materials, modifying the design to improve the fit, and providing a greater range of sizes.

Adolescent↗

PubMed2004

Elliptical selection experiment for the estimation of genetic parameters of the growth rate and feed conversion ratio in rabbits.

Two elliptical selection experiments were performed in two contemporary sire lines of rabbits (C and R) in order to optimize the experimental design for estimating the genetic parameters of the growth rate (GR) and feed conversion ratio (FCR). Twelve males and 19 females from line C, and 13 males and 23 females from line R, were selected from an ellipse defined by a quadratic index based on these traits. Data from 160 rabbits of each of the parental generations of lines C and R and their offspring (275 and 266 animals, respectively) were used for the analysis. A Bayesian framework was adopted for inference. Marginal posterior distributions of the genetic parameters were obtained by Gibbs sampling. An animal model including batch, parity order, litter size, and common environmental litter effects was assumed. Posterior means (posterior standard deviations) for heritabilities of GR and FCR were estimated to be 0.31 (0.10) and 0.31 (0.10), respectively, in line C and 0.21 (0.08) and 0.25 (0.12) in line R. Posterior means of the proportion of the variance due to common litter environmental effects were 0.14 (0.06) and 0.21 (0.06) for GR and FCR, respectively, in line C and 0.17 (0.06) and 0.22 (0.06) in line R. Posterior means of genetic correlation between both traits were -0.49 (0.25) in line C and -0.47 (0.32) in line R, indicating that selection for GR was expected to result in a similar correlated response in FCR in both lines.

Animal Feed↗

PubMedDate not supplied

Comparison of linear and nonlinear classification algorithms for the prediction of drug and chemical metabolism by human UDP-glucuronosyltransferase isoforms.

Partial least squares discriminant analysis (PLSDA), Bayesian regularized artificial neural network (BRANN), and support vector machine (SVM) methodologies were compared by their ability to classify substrates and nonsubstrates of 12 isoforms of human UDP-glucuronosyltransferase (UGT), an enzyme "superfamily" involved in the metabolism of drugs, nondrug xenobiotics, and endogenous compounds. Simple two-dimensional descriptors were used to capture chemical information. For each data set, 70% of the data were used for training, and the remainder were used to assess the generalization performance. In general, the SVM methodology was able to produce models with the best predictive performance, followed by BRANN and then PLSDA. However, a small number of data sets showed either equivalent or better predictability using PLSDA, which may indicate relatively linear relationships in these data sets. All SVM models showed predictive ability (>60% of test set predicted correctly) and five out of the 12 test sets showed excellent prediction (>80% prediction accuracy). These models represent the first use of pattern recognition methods to discriminate between substrates and nonsubstrates of human drug metabolizing enzymes and the first thorough assessment of three classification algorithms using multiple metabolic data sets.

Algorithms↗

PubMed2004

Mining microarray data to identify transcription factors expressed in naïve resting but not activated T lymphocytes.

Transcriptional repressors controlling the expression of cytokine genes have been implicated in a variety of physiological and pathological phenomena. An unknown repressor that binds to the distal NFAT element of the interleukin-2 (IL-2) gene promoter in naive T-helper lymphocytes has been implicated in autoimmune phenomena and has emerged as a potentially important factor controlling the latency of HIV-1. The aim of this paper was the identification of this repressor. We resorted to public microarray databases looking for DNA-binding proteins that are present in naïve resting T cells but are downregulated when the cells are activated. A Bayesian data mining statistical analysis uncovered 25 candidate factors. Of the 25, NFAT4 and the oncogene ets-2 bind to the common motif AAGGAG found in the HIV-1 LTR and IL-2 probes. Ets-2 binding site contains the three G's that have been shown to be important for binding of the unknown factor; hence, we considered it the likeliest candidate. Electrophoretic mobility shift assays confirmed cross-reactivity between the unknown repressor and anti-ets-2 antibodies, and cotransfection experiments demonstrated the direct involvement of Ets-2 in silencing the IL-2 promoter. Designing experiments for transcription factor analysis using microarrays and Bayesian statistical methodologies provides a novel way toward elucidation of gene control networks.

CD4-Positive T-Lymphocytes↗

PubMed2004

Molecular phylogeny and character evolution in the Western Palaearctic Helicidae s.l. (Gastropoda: Stylommatophora).

In this study, we present a molecular phylogeny for the west Palaearctic Helicidae sensu lato based on sequence data from two mitochondrial (COI, 16S rDNA) and two nuclear (ITS-1, 18S rDNA) genes. Maximum likelihood analysis and Bayesian inference revealed well supported monophyletic clades partly conflicting traditional classifications. Based on these results, we propose the following system. The Western Palaearctic Helicidae s.l. consist of two families, Helicidae and Hygromiidae. Within the Helicidae, three well supported subfamilies can be recognised: the Helicinae, Ariantinae, and Helicodontinae. The Hygromiidae consist of three clades: the Hygromiinae, the Helicellinae, and a yet unnamed clade comprising the genera Sphincterochila and Cochlicella. We then used the phylogeny to study the evolution of anatomical, and ecological characters traditionally used for systematic classification. In the Helicidae s.l., two independent evolutionary transitions to life in xeric environments occurred, which allowed the occupation of new niches with a subsequent radiation of the Helicellinae-Cochlicella/Sphincterochila clade and the Helicinae. Whereas, the multiplication of the Glandulae mucosae is a synapomorphy of the Hygromiidae, the lovedart sac apparatus is present in all groups and thus, the trait cannot provide a synapomorphy for either families or subfamilies. Additionally, we evaluated the use of structural molecular genetic characters for taxonomic assessment. The presence of an unique loop region of the 16S rDNA gene and a short tandem repeat in the ITS-1 region provide independent evidence for the monophyly of these major two groups, and can be used for preliminary classification.

Animals↗

PubMed2026

Building phenotypic character matrices for phylogenetic inference: exploration of 35 years of practice.

Recent methodological development in phylogenetic inference has focused predominantly on molecular data. However, renewed interest in other data types, particularly morphological data, has followed from the increased recognition of the power of total evidence and tip-dating approaches, including fossil data, for inference of time-scaled trees and rates of evolution. However, attention has largely focused on the improvement of models of morphological evolution and other analytical tools with much less discussion about data acquisition itself. Here we review past and current practice for describing and collecting morphological data for phylogenetic inference. We present a systematic review of 164 phylogenetic analyses conducted over the last 35 years and focused on a diverse group of extinct arthropods: trilobites. Trends in increasing matrix size, data type, and coding strategy are evident. Where present, polymorphic characters have been predominantly derived from discretized continuous characters, although increasingly practitioners are utilizing alternative approaches for the treatment of quantitative characters. Not surprisingly, traditional indices that describe character consistency are highly correlated with matrix size but show surprising variation at different taxonomic scales. More recent attempts to describe data quality using information theory imply that characters can have high information content even if data are missing for many tips, providing support against the exclusion of characters because of missing data. In consideration of this, as well as advances in the study of developmental biology and variational complexity, we identify several avenues for increasing the quality and quantity of morphological data going forward.

Phylogeny↗

PubMed1997

Consensus analysis: reliability, validity, and informant accuracy in use of American and Mandarin Chinese pain descriptors.

A quantitative method for validating qualitative interview results and checking sample parameters is described and illustrated using common pain descriptions among a sample of Anglo-American and mandarin Chinese patients and dentists matched by age and gender. Assumptions were that subjects were members of a sociocultural group (e.g. ethnic or professional/lay) and answered questions independently about a monotonic domain (e.g. pain). Subjects answered 18 true/false items derived from and selected to reflect pain perceptions consistent with published and unpublished interview data. Estimates of consistency in use of descriptors within groups, validity of description, accuracy of individuals compared with others in their group, and minimum required sample size were calculated using Cronbach's alpha, factor analysis, and Bayesian probability. Ethnic and professional differences within and across groups were also tested using multidimensional scaling (MDS) and hypothesis testing. Consensus (consistency of subject response by group) was .99 among Anglo-Americans and .97 among Chinese. Mean subject accuracy was .81 for Americans and .57 for Chinese, indicating the need for larger numbers of Chinese to supplement each others' statements. However, larger numbers of subjects were recruited than actually required for each ethnic group at .95 confidence limits. MDS showed similarities in use of descriptors within ethnic groups, while there were differences (p < .001) between Chinese and American groups. Use of covalidating questionnaires that reflect results of qualitative interviews are recommended in order to estimate sample parameters such as intersubject agreement, individual subject accuracy, and minimum required sample sizes.

Adult↗