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PubMed2005

Molecular studies of photobionts of selected lichens from the coastal vegetation of Brazil.

A light microscopic and molecular analysis of photobionts in Ramalina and Cladonia from coastal habitats of Brazil is presented. A Bayesian phylogenetic analysis of ITS rDNA sequences suggests a Trebouxia lineage which is preferentially tropical in geographic distribution. This highly diverse clade also includes the morphological similar species Trebouxia higginsiae and galapagensis. Within the predominantly tropical clade of Trebouxia we distinguish several subclades, three of which are represented in our samples of Ramalina species. Since sexuality has not been recognized in coccal lichenised photobionts until recently, we cannot apply a biological species concept, but when compared with the sequence diversity between known species we conclude that several new species need to be described in this clade. The mutually exclusive presence of other Trebouxia lineages in temperate samples of Ramalina suggests an evolution towards higher selectivity in this genus. A strictly tropical lineage is not conspicuous in the photobionts of the genus Asterochloris sampled from Cladonia so far.

Base Sequence↗

PubMed2025

Identification of a PRDM1-regulated T cell network to regulate atherosclerotic plaque inflammation.

BACKGROUND: Inflammation is a key driver of atherosclerosis, yet the mechanisms sustaining inflammation in human plaques remain poorly understood. This study uses a network-based approach to identify immune gene programs involved in the transition from low- to high-risk (rupture-prone) human atherosclerotic plaques. METHODS: Expression data from human carotid artery plaques, both stable (low-risk, n = 16) and unstable (high-risk, n = 27), were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA). Bayesian network inference, operated on the eigengene values from the WGCNA, further extended the WGCNA analysis, and similarity to the signature of T cell subsets was validated in single-cell RNA sequencing data of human plaques, and a loss-of-function study in a mouse model of atherosclerosis. In silico drug repurposing was performed to identify potential therapeutic targets. RESULTS: Our analysis revealed a distinct gene module with a prominent T cell signature, particularly in unstable plaques. Key regulatory factors, RUNX3, IRF7 and in particular PRDM1, were significantly downregulated in plaque T cells from symptomatic versus asymptomatic patients, indicating a protective role. Additionally, as PRDM1 is downstream of IRF7, we opted for PRDM1 as a key target. T cell-specific Prdm1 deficiency in Western-type diet fed Ldlr knockout mice featured accelerated plaque progression. Finally, as PRDM1 targeting drugs are not yet available, we performed in silico drug repurposing, identifying EGFR inhibitors as promising therapeutic candidates. CONCLUSIONS: This study highlights a PRDM1-regulated T cell network that distinguishes high-risk from low-risk plaques and demonstrates the regulatory role of T cell PRDM1 in controlling atherosclerosis, positioning this pathway as a promising therapeutic target.

Plaque, Atherosclerotic↗

PubMed2001

A Bayesian approach to stochastic cost-effectiveness analysis. An illustration and application to blood pressure control in type 2 diabetes.

The aim of this paper is to discuss the use of Bayesian methods in cost-effectiveness analysis (CEA) and the common ground between Bayesian and traditional frequentist approaches. A further aim is to explore the use of the net benefit statistic and its advantages over the incremental cost-effectiveness ratio (ICER) statistic. In particular, the use of cost-effectiveness acceptability curves is examined as a device for presenting the implications of uncertainty in a CEA to decision makers. Although it is argued that the interpretation of such curves as the probability that an intervention is cost-effective given the data requires a Bayesian approach, this should generate no misgivings for the frequentist. Furthermore, cost-effectiveness acceptability curves estimated using the net benefit statistic are exactly equivalent to those estimated from an appropriate analysis of ICERs on the cost-effectiveness plane. The principles examined in this paper are illustrated by application to the cost-effectiveness of blood pressure control in the U.K. Prospective Diabetes Study (UKPDS 40). Due to a lack of good-quality prior information on the cost and effectiveness of blood pressure control in diabetes, a Bayesian analysis assuming an uninformative prior is argued to be most appropriate. This generates exactly the same cost-effectiveness results as a standard frequentist analysis.

Bayes Theorem↗

PubMed1991

A three-step approach combining Bayesian regression and NONMEM population analysis: application to midazolam.

NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1 were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence VSS or intercompartmental clearance.

Adolescent↗

PubMed2000

Bayesian detection and modeling of spatial disease clustering.

Many current statistical methods for disease clustering studies are based on a hypothesis testing paradigm. These methods typically do not produce useful estimates of disease rates or cluster risks. In this paper, we develop a Bayesian procedure for drawing inferences about specific models for spatial clustering. The proposed methodology incorporates ideas from image analysis, from Bayesian model averaging, and from model selection. With our approach, we obtain estimates for disease rates and allow for greater flexibility in both the type of clusters and the number of clusters that may be considered. We illustrate the proposed procedure through simulation studies and an analysis of the well-known New York leukemia data.

Bayes Theorem↗

PubMed1998

Approximate Bayesian inference for random effects meta-analysis.

Whilst meta-analysis is becoming a more commonplace statistical technique, Bayesian inference in meta-analysis requires complex computational techniques to be routinely applied. We consider simple approximations for the first and second moments of the parameters of a Bayesian random effects model for meta-analysis. These computationally inexpensive methods are based on simple analytical formulae that provide an efficient tool for a qualitative analysis and a quick numerical estimation of posterior quantities. They are shown to lead to sensible approximations in two examples of meta-analyses and to be in broad agreement with the more computationally intensive Gibbs sampling.

Antibiotic Prophylaxis↗

PubMed1992

Meta-analysis for 2 x 2 tables: a Bayesian approach.

This paper develops and implements a fully Bayesian approach to meta-analysis, in which uncertainty about effects in distinct but comparable studies is represented by an exchangeable prior distribution. Specifically, hierarchical normal models are used, along with a parametrization that allows a unified approach to deal easily with both clinical trial and case-control study data. Monte Carlo methods are used to obtain posterior distributions for parameters of interest, integrating out the unknown parameters of the exchangeable prior or 'random effects' distribution. The approach is illustrated with two examples, the first involving a data set on the effect of beta-blockers after myocardial infarction, and the second based on a classic data set comprising 14 case-control studies on the effects of smoking on lung cancer. In both examples, rather different conclusions from those previously published are obtained. In particular, it is claimed that widely used methods for meta-analysis, which involve complete pooling of 'O-E' values, lead to understatement of uncertainty in the estimation of overall or typical effect size.

Adrenergic beta-Antagonists↗

PubMed2016

A probabilistic generative model for quantification of DNA modifications enables analysis of demethylation pathways.

We present a generative model, Lux, to quantify DNA methylation modifications from any combination of bisulfite sequencing approaches, including reduced, oxidative, TET-assisted, chemical-modification assisted, and methylase-assisted bisulfite sequencing data. Lux models all cytosine modifications (C, 5mC, 5hmC, 5fC, and 5caC) simultaneously together with experimental parameters, including bisulfite conversion and oxidation efficiencies, as well as various chemical labeling and protection steps. We show that Lux improves the quantification and comparison of cytosine modification levels and that Lux can process any oxidized methylcytosine sequencing data sets to quantify all cytosine modifications. Analysis of targeted data from Tet2-knockdown embryonic stem cells and T cells during development demonstrates DNA modification quantification at unprecedented detail, quantifies active demethylation pathways and reveals 5hmC localization in putative regulatory regions.

5-Methylcytosine↗

PubMed2002

Microarray analysis of corneal fibroblast gene expression after interleukin-1 treatment.

PURPOSE: To identify changes in gene expression in human corneal fibroblasts after exposure to interleukin-1alpha. METHODS: RNA was isolated from cultured human corneal fibroblasts after treatment with interleukin-1alpha and subjected to DNA microarray analysis. Changes in gene expression were determined by comparison with untreated cells in three independent experiments after a Bayesian statistical analysis of variance. RESULTS: Changes in gene expression were reproducibly observed in 165 genes representing previously identified and novel chemokines, matrix molecules, membrane receptors, angiogenic mediators, and transcription factors that correlated with pathophysiological responses to inflammation. Dramatic increases in gene expression were observed with exodus-1 (CCL20), MMP-12, and RhoA. CONCLUSIONS: DNA microarray analysis of the corneal fibroblast response to interleukin-1alpha provides important insight into modeling changes in gene expression and suggests novel therapeutic targets for the control of corneal inflammation.

Cells, Cultured↗

PubMed2005

Wide-range analysis of genetic structure of Betula maximowicziana, a long-lived pioneer tree species and noble hardwood in the cool temperate zone of Japan.

Betula maximowicziana is a long-lived pioneer tree species in Japanese cool temperate forests that plays an important role in maintenance of the forest ecosystem and has high economic value. Here we assess the wide-range genetic structure of 23 natural populations of B. maximowicziana using 11 simple sequence repeat (SSR) loci. Genetic diversity within populations was relatively low in all populations (mean H(E), 0.361; mean allelic richness, 2.80; mean rare allelic richness, 1.02). The population differentiation was also relatively low (F(ST), 0.062). Genetic distance-based and Bayesian clustering analysis revealed that the populations examined here could be divided into a southern group and a northern group. Analysis of rare allelic richness and Bayesian clustering revealed evidence for both southern and northern refugia during the last glacial period. Furthermore, a comparison of regional genetic diversity revealed significant clines in allelic richness. In spatial genetic structure evaluation, significant isolation by distance (IBD) was detected among the 23 populations, but not within regions. Moreover, significant population bottlenecks were found in all populations under infinite allele model (IAM) assumptions. These unusual, significant bottlenecks might be because of the processes of postglacial colonization and the species' characters and/or life history as a long-lived pioneer tree species. The wide-range, regional genetic structure found in this study provides an important baseline for conservation and forest management, including the identification of evolutionarily significant units (ESUs) and/or management units (MUs) of B. maximowicziana.

Bayes Theorem↗

PubMed2003

Bayesian approaches to multiple sources of evidence and uncertainty in complex cost-effectiveness modelling.

Increasingly complex models are being used to evaluate the cost-effectiveness of medical interventions. We describe the multiple sources of uncertainty that are relevant to such models, and their relation to either probabilistic or deterministic sensitivity analysis. A Bayesian approach appears natural in this context. We explore how sensitivity analysis to patient heterogeneity and parameter uncertainty can be simultaneously investigated, and illustrate the necessary computation when expected costs and benefits can be calculated in closed form, such as in discrete-time discrete-state Markov models. Information about parameters can either be expressed as a prior distribution, or derived as a posterior distribution given a generalized synthesis of available data in which multiple sources of evidence can be differentially weighted according to their assumed quality. The resulting joint posterior distributions on costs and benefits can then provide inferences on incremental cost-effectiveness, best presented as posterior distributions over net-benefit and cost-effectiveness acceptability curves. These ideas are illustrated with a detailed running example concerning the cost-effectiveness of hip prostheses in different age-sex subgroups. All computations are carried out using freely available software for conducting Markov chain Monte Carlo analysis.

Adult↗

PubMed2026

Daily low-dose carboplatin or weekly carboplatin plus nab-paclitaxel for concurrent chemoradiotherapy in older patients with locally advanced non-small cell lung cancer (JCOG1914): A randomized phase 3 trial.

BACKGROUND: Daily low-dose carboplatin with concurrent thoracic radiotherapy is the standard treatment for older patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) in Japan. METHODS: This open-label phase 3 trial was conducted at 38 institutions in Japan. Patients aged ≥ 75 years with LA-NSCLC were randomly assigned (1:1) to receive daily carboplatin (30 mg/m2) or weekly carboplatin (area under the curve, 2 mg·min/mL) plus nab-paclitaxel (30 mg/m2) with thoracic radiotherapy. Durvalumab maintenance therapy was recommended after treatment completion. The primary endpoint was overall survival, which was used to assess the non-inferiority of weekly carboplatin plus nab-paclitaxel compared to daily low-dose carboplatin. RESULTS: From December 2020 to March 2024, 124 patients were enrolled (carboplatin arm, 61 and carboplatin plus nab-paclitaxel arm, 63). In the planned interim analysis, the Bayesian predictive probability indicating the non-inferiority of carboplatin plus nab-paclitaxel compared with carboplatin in the final analysis was 8.0%, leading to early study termination for futility. The median overall survival was not estimable in the carboplatin arm; the estimated value in the carboplatin plus nab-paclitaxel arm was 26.1 months (hazard ratio, 1.56; 95% confidence interval, 0.79-3.11; p = 0.200). Two treatment-related and seven non-cancer-related deaths occurred in the carboplatin plus nab-paclitaxel arm. Patients in the carboplatin arm had better quality of life than those in the carboplatin plus nab-paclitaxel arm at 6 weeks (odds ratio, 0.39; 95% confidence interval, 0.18-0.81; p = 0.012). CONCLUSIONS: Daily low-dose carboplatin with concurrent thoracic radiotherapy remains the standard treatment for older patients with unresectable LA-NSCLC in Japan.

Humans↗

PubMed2004

Detection of diffuse abnormal perfusion in SPECT using a normal brain atlas.

Visual assessment, with significant inter- or intraobserver variability, is still the norm for the evaluation of Single Photon Emission Computerized Tomography (SPECT) cerebral perfusion studies. We present in this paper an automated method for screening SPECT studies to detect diffuse disseminated abnormalities based on a computerized atlas of normal regional cerebral blood flow (rCBF). To generate the atlas, a set of normal brain SPECT studies are registered together. The atlas contains the intensity mean, the nonlinear displacement mean, and the variance of the activity pattern. A patient is then evaluated by registering his or her SPECT volume to the atlas and computing the nonlinear 3-D displacement of each voxel needed for the best shape fit to it. A voxel is counted as "abnormal" if the intensity difference between the atlas and the registered patient (or if the 3-D motion necessary to move the voxel to its registered position) is superior to 3 SD of normal mean. The number of abnormal voxels is used to classify studies. We validated this approach on 24 SPECT perfusion studies selected visually for having clear diffuse anomalies and 21 normal studies. A Markovian segmentation algorithm is also used to identify the white and gray matters for regional analysis. Based on the number of abnormal voxels, two supervised classifiers were tested: (1) minimum distance-to-mean and (2) Bayesian. The analysis of the intensity and displacement "abnormal" voxels allow one to achieve an 80% correct classification rate for the whole brain and a 93% rate if we consider only voxels in the segmented gray matter region.

Algorithms↗

PubMed2001

Bayesian value-of-information analysis. An application to a policy model of Alzheimer's disease.

A framework is presented that distinguishes the conceptually separate decisions of which treatment strategy is optimal from the question of whether more information is required to inform this choice in the future. The authors argue that the choice of treatment strategy should be based on expected utility, and the only valid reason to characterize the uncertainty surrounding outcomes of interest is to establish the value of acquiring additional information. A Bayesian decision theoretic approach is demonstrated through a probabilistic analysis of a published policy model of Alzheimer's disease. The expected value of perfect information is estimated for the decision to adopt a new pharmaceutical for the population of patients with Alzheimer's disease in the United States. This provides an upper bound on the value of additional research. The value of information is also estimated for each of the model inputs. This analysis can focus future research by identifying those parameters where more precise estimates would be most valuable and indicating whether an experimental design would be required. We also discuss how this type of analysis can also be used to design experimental research efficiently (identifying optimal sample size and optimal sample allocation) based on the marginal cost and marginal benefit of sample information. Value-of-information analysis can provide a measure of the expected payoff from proposed research, which can be used to set priorities in research and development. It can also inform an efficient regulatory framework for new healthcare technologies: an analysis of the value of information would define when a claim for a new technology should be deemed substantiated and when evidence should be considered competent and reliable when it is not cost-effective to gather any more information.

Alzheimer Disease↗

PubMed2002

Spatial and object working memory impairments in schizophrenia patients: a Bayesian item-response theory analysis.

This study reports evidence that schizophrenia patients are significantly impaired in both spatial and object (shape) working memory. A 3-s delay between exposure and recall of targets was used and Bayesian item-response theory was applied to compensate for the tasks' differential difficulty while simultaneously taking account of missing data from participant attrition. Weaker evidence was found that in schizophrenia both domains are equally impaired on average, that spatial and object working memory appear to be more highly correlated with each other in the schizophrenia population than in the normal population, and that schizophrenia patients show greater variability in spatial than object working memory performance.

Adult↗

PubMed2003

Sarcoma and familial retinoblastoma.

BACKGROUND: Retinoblastoma is the most common malignant ocular tumour of childhood. It results from mutations in the retinoblastoma gene, RB1, which may be sporadic or heritable. Only 10-25% of patients have a family history of retinoblastoma and can be assumed to have a heritable RB1 mutation. A small proportion of the remaining patients may have a heritable mutation despite the lack of relatives with retinoblastoma. Heritable RB1 mutations are associated with an increased risk of sarcoma. Described herein are three patients with a past history of retinoblastoma, no family history of retinoblastoma, and a first-degree relative with sarcoma. Mutation analyses were performed on DNA samples from these patients to test for heritable RB1 mutations. METHODS: A genomic DNA analysis of RB1 gene. RESULTS: Heritable mutations in the RB1 gene were identified in two of the three cases. In these two cases, Bayesian risk calculation indicated that the chance of the affected relatives having the familial RB1 mutation was greater than 90%. In the case without an identified mutation, Bayesian risk analysis indicated that the chance of there being an unidentified familial RB1 mutation was low (16%) but could still be clinically significant in managing the family. CONCLUSION: The risk of non-ocular malignancies and the availability of genetic testing for heritable RB1 mutations have important clinical implications for the management of children with retinoblastoma.

Adult↗

PubMed1994

Transient ischemic attacks, carotid stenosis, and an incidental intracranial aneurysm. A decision analysis.

Three patients with transient ischemic attacks (TIAs), a stenotic or ulcerating carotid lesion, and an unruptured aneurysm are discussed. Decision analysis is used in comparing treatment strategies for each patient: clipping of the aneurysm, endarterectomy, or both, with or without platelet aggregation inhibitors. Bayesian sensitivity analysis with Monte Carlo simulation is used to estimate 95% confidence limits for the difference in discounted quality-adjusted life expectancy between the treatment strategies. Platelet-inhibiting therapy is indicated for all three patients, despite the increased risk of complications from subarachnoid hemorrhage. Carotid endarterectomy cannot be recommended for any of the three patients. With regard to aneurysm surgery, a toss-up exists in one patient; in another, the aneurysm should be clipped; and in one, the decision depends on the probability that the TIAs originate from the aneurysm. Guidelines for the management of similar patients are given. For patients with TIAs, a moderate carotid stenosis, and an intracranial aneurysm that does not seem to be related to the symptoms, neither clipping of the aneurysm nor endarterectomy can be recommended with confidence; however, when the intracranial aneurysm is just as likely to be the source of the TIAs as not, clipping is recommended up to the age of 70, when the surgical risks are moderately high.

Aged↗

PubMed2004

Domain shuffling has been the main mechanism forming new hominoid killer cell Ig-like receptors.

The killer cell Ig-like receptor (KIR) gene family encodes MHC class I-specific receptors, which regulate NK cell responses and are also expressed on subpopulations of T cells. KIR haplotypes vary in gene content, which, in combination with allelic polymorphism, extensively diversifies the KIR genotype both within and between human populations. Species comparison indicates that formation of new KIR genes and loss of old ones are frequent events, so that few genes are conserved even between closely related species. In this regard, the hominoids define a time frame that is particularly informative for understanding the processes of KIR evolution and its potential impact on killer cell biology. KIR cDNA were characterized from PBMC of three gorillas, and genomic DNA were characterized for six additional individuals. Eleven gorilla KIR genes were defined. With attainment of these data, a set of 75 KIR sequences representing five hominoid species was assembled, which also included rhesus monkey, cattle, and rodent KIR. Searching this data set for recombination events, and phylogenetic analysis using Bayesian methods, demonstrated that new KIR were usually the result of recombination between loci in which complete protein domains were shuffled. Further phylogenetic analysis of the KIR sequences after removal of confounding recombined segments showed that only two KIR genes, KIR2DL4 and KIR2DL5, have been preserved throughout hominoid evolution, and one of them, KIR2DL4, is also common to rhesus monkey and hominoids. Other KIR genes represent recombinant forms present in a minority of species, often only one, as exemplified by 8 of the 11 gorilla KIR genes.

Animals↗