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Modelling the cumulative risk for a false-positive under repeated screening events.

Screening examinations are widely utilized in detecting the presence of medical disorders, for instance, screening mammograms and clinical breast examinations for detection of breast cancer. Such procedures are invaluable in enabling early treatment but produce the possibilities of false-positive and false-negative diagnoses. Focusing on false-positive results, with increasing number of screening events, it is clear that the risk of a false-positive increases. The objective of this paper is to quantify the cumulative risk associated with repeated screening. We provide a very general framework within which to investigate this risk, both at the population and the individual level. The latter allows incorporation of evolving patient medical history to permit individualized assessment of risk. We model cumulative risk in terms of the number of screening events until first false-positive. We develop models which are essentially familiar actuarial models for life table data adding a Cox regression to enable individual level modelling. Because it offers several advantages, we employ a Bayesian inference framework and apply our modelling to the analysis of 9773 screening mammograms collected from 2227 women at an HMO serving nearly 300000 adults in and around Boston, MA.

Adult↗

Variance components analysis for pedigree-based censored survival data using generalized linear mixed models (GLMMs) and Gibbs sampling in BUGS.

Complex human diseases are an increasingly important focus of genetic research. Many of the determinants of these diseases are unknown and there is often a strong residual covariance between relatives even when all known genetic and environmental factors have been taken into account. This must be modeled correctly whether scientific interest is focused on fixed effects, as in an association analysis, or on the covariance structure itself. Analysis is straightforward for multivariate normally distributed traits, but difficulties arise with other types of trait. Generalized linear mixed models (GLMMs) offer a potentially unifying approach to analysis for many classes of phenotype including right censored survival times. This includes age-at-onset and age-at-death data and a variety of other censored traits. Markov chain Monte Carlo (MCMC) methods, including Gibbs sampling, provide a convenient framework within which such GLMMs may be fitted. In this paper, we use BUGS ("Bayesian inference using Gibbs sampling": a readily available, generic Gibbs sampler) to fit GLMMs for right-censored survival times in nuclear and extended families. We discuss parameter interpretation and statistical inference, and show how to circumvent a number of important theoretical and practical problems. Using simulated data, we show that model parameters are consistent. We further illustrate our methods using data from an ongoing cohort study. Finally, we propose that the random effects associated with a genetic component of variance (e.g., sigma(2)(A)) in a GLMM may be regarded as an adjusted "phenotype" and used as input to a conventional model-based or model-free linkage analysis. This provides a simple way to conduct a linkage analysis for a trait reflected in a right-censored survival time while comprehensively adjusting for observed confounders at the level of the individual and latent environmental effects shared across families.

Bayes Theorem↗

Insights Into the Structural Features, Codon Usage Patterns, and Phylogenetic Analysis in Neoniphon argenteus (Teleostei: Holocentriformes) Based on Complete Mitochondrial Genome.

Neoniphon argenteus, a widely distributed nocturnal coral reef fish in the family Holocentridae, plays an important role in maintaining coral reef ecosystem health, yet its phylogenetic position remains poorly resolved. To bridge this gap, we sequenced and analyzed the complete mitochondrial genome of a specimen from the South China Sea to characterize its structural features, codon usage patterns, and phylogenetic relationships. The 16,569 bp mitogenome (GenBank: PP190474.1) encodes 13 protein-coding genes (PCGs), 22 tRNAs, two rRNAs, and two non-coding regions, exhibiting a distinct A + T bias. All tRNAs fold into typical cloverleaf secondary structures except tRNA-Ser (AGN), which lacks the dihydrouridine (DHU) arm. The control region contains palindromic motifs (TACAT/ATGTA) capable of forming hairpin structures and five conserved sequence blocks, whereas the OL region harbors a conserved 5'-GCCGG-3' motif. RSCU analysis revealed 31 frequently used codons (RSCU > 1) with a pronounced preference for A/C-ending codons. The ΔRSCU method identified 10 candidate optimal codons (GCA, CAA, GAA, GGA, AUU, CUA, CCA, CGA, ACA, and GUC). Selection pressure analysis using EasyCodeML and site-specific models indicated that all PCGs are predominantly under purifying selection, with no significant evidence of pervasive positive selection. ND6 exhibited elevated pairwise Ka/Ks ratios (mean = 1.209 ± 0.047), consistent with reduced selective constraint rather than adaptive evolution. Phylogenetic analysis of 19 Holocentriformes species using maximum likelihood and Bayesian inference with partitioned models based on 13 PCGs and two rRNA genes (12S and 16S) assigned all taxa to two well-supported subfamilies (Holocentrinae and Myripristinae). Within Holocentrinae, Neoniphon species form a monophyletic clade nested within a paraphyletic Sargocentron, suggesting that the genus Sargocentron as currently defined is not monophyletic. This study provides useful baseline molecular data for further exploration of the evolutionary history of N. argenteus and other members of Holocentriformes.

Holocentridae↗

Bayesian technique for investigating linearity in event-related BOLD fMRI.

Event-related BOLD fMRI data is modeled as a linear time-invariant system. Together with Bayesian inference techniques, a statistical test is developed for rigorously detecting linearity/nonlinearity in the BOLD response system. The test is applied to data collected from eight subjects using an event-related paradigm with a switching checkerboard as the visual stimulus. Analyzed as a group, the results clearly find the response to be nonlinear. When each subject is analyzed individually, however, the results are predominantly nonlinear, but there is some evidence to suggest that there may be a crossover from a linear to a nonlinear regime and vice versa. This could be important when estimating physiological parameters for individuals. Additionally, estimates of the hemodynamic response function and corresponding response were obtained, but there was no consistent appearance of a poststimulus undershoot in the event-related BOLD response.

Adult↗

Estimation of infection and recovery rates for highly polymorphic parasites when detectability is imperfect, using hidden Markov models.

A Bayesian hierarchical model is proposed for estimating parasitic infection dynamics for highly polymorphic parasites when detectability of the parasite using standard tests is imperfect. The parasite dynamics are modelled as a non-homogeneous hidden two-state Markov process, where the observed process is the detection or failure to detect a parasitic genotype. This is assumed to be conditionally independent given the hidden process, that is, the underlying true presence of the parasite, which evolves according to a first-order Markov chain. The model allows the transition probabilities of the hidden states as well as the detectability parameter of the test to depend on a number of covariates. Full Bayesian inference is implemented using Markov chain Monte Carlo simulation. The model is applied to a panel data set of malaria genotype data from a randomized controlled trial of bed nets in Tanzanian children aged 6-30 months, with the age of the host and bed net use as covariates. This analysis confirmed that the duration of infections with parasites belonging to the MSP-2 FC27 allelic family increased with age.

Algorithms↗

Markov modelling of changes in HIV-specific cytotoxic T-lymphocyte responses with time in untreated HIV-1 infected patients.

HIV-specific cytotoxic CD8(+) T-lymphocytes (CTL) appear to be the cornerstone of the immune response to HIV infection. Recent studies show that CTL activity reflects patients' anti-HIV immune status and slows disease progression. However, the dynamics of the diversity of this response also appears as a key parameter for immune control but the dynamics of this diversity is largely undocumented. We modelled changes in CTL responses against the seven principal HIV proteins over time. We also studied the influence of plasma viral load on temporal changes in HIV protein recognition by memory CTL. The generic model we developed is based on a continuous time homogeneous Markov process with reversible states. Those states are defined by the number of proteins recognized by memory CTL in a given patient at a given time. This approach was developed within a Bayesian framework. Full Bayesian inference is implemented using Markov chain Monte Carlo simulations (MCMC). The Gibbs sampling algorithm was used to estimate the marginal posterior distributions of the transition intensities between stages of CTL responses. We applied our model to data of 152 HIV-infected patients included in the IMMUNOCO cohort. The model suggested that the diversity of HIV protein recognition by memory CTL in treatment-naive patients decreases as the disease progresses. Namely, the loss of T cytotoxic responses is globally faster than their acquisition. Indeed, these patients' T cytotoxic responses were characterized by marked individual turnover and a gradual loss of multiple protein recognition over time, this loss accelerating as viral load increased.

Adult↗

The utility of prior information and stratification for parameter estimation with two screening tests but no gold standard.

When a gold standard screening or diagnostic test is not routinely available, it is common to apply two different imperfect tests to subjects from a study population. There is a considerable literature on estimating relevant parameters from the resultant data. In the situation that test sensitivities and specificities are unknown, several inferential strategies have been proposed. One suggestion is to use rough knowledge about the unknown test characteristics as prior information in a Bayesian analysis. Another suggestion is to obtain the statistical advantage of an identified model by splitting the population into two strata with differing disease prevalences. There is some division of opinion in the epidemiological literature on the relative merits of these two approaches. This article aims to shed light on the issue, by applying some recently developed theory on the performance of Bayesian inference in non-identified statistical models.

Bayes Theorem↗

Analysis of the renal transplant waiting list in the País Valencià (Spain).

In this paper we analyse the renal transplant waiting list of the País Valencià in Spain, using Queueing theory. The customers of this queue are patients with end-stage renal failure waiting for a kidney transplant. We set up a simplified model to represent the flow of the customers through the system, and perform Bayesian inference to estimate parameters in the model. Finally, we consider several scenarios by tuning the estimations achieved and computationally simulate the behaviour of the queue under each one. The results indicate that the system could reach equilibrium at some point in the future and the model forecasts a slow decrease in the size of the waiting list in the short and middle term.

Bayes Theorem↗

Bayesian proportional hazards model with time-varying regression coefficients: a penalized Poisson regression approach.

One can fruitfully approach survival problems without covariates in an actuarial way. In narrow time bins, the number of people at risk is counted together with the number of events. The relationship between time and probability of an event can then be estimated with a parametric or semi-parametric model. The number of events observed in each bin is described using a Poisson distribution with the log mean specified using a flexible penalized B-splines model with a large number of equidistant knots. Regression on pertinent covariates can easily be performed using the same log-linear model, leading to the classical proportional hazard model. We propose to extend that model by allowing the regression coefficients to vary in a smooth way with time. Penalized B-splines models will be proposed for each of these coefficients. We show how the regression parameters and the penalty weights can be estimated efficiently using Bayesian inference tools based on the Metropolis-adjusted Langevin algorithm.

Bayes Theorem↗

Comparison of the information in two lung function experiments.

The amount of ventilation relative to perfusion (the ventilation-perfusion ratio) received by the lung is a useful indicator of the efficiency of lung function. Two alternative techniques for recovering the ventilation-perfusion ratio are outlined. While both techniques rely on the use of inert gases, one is well established and the other is only in a developmental stage. This paper focuses on a comparison of the amount of statistical information provided by these two techniques about the ventilation-perfusion ratio. The criterion applied here for measuring amount of information has roots in communication theory and uses ideas inherent to Bayesian inference.

Bayes Theorem↗

The pattern of variation in centipede segment number as an example of developmental constraint in evolution

The range of animal morphologies observed in nature is partly determined by natural selection. However, there is no agreement yet regarding whether it is also partly determined by developmental constraint. Testing for the effects of constraint has been difficult due to the lack of both an appropriate null model and a sufficiently simple system capable of yielding unambiguous results regarding the model's plausibility. Here we examine the case of variation in segment number in geophilomorph centipedes. Curiously, while this ranges between 29 and 191, there are no species in which an even number of segments is observed, in contrast to about 1000 species with odd numbers of segments. It seems unlikely that this distribution of character values is determined by selection alone. Using an approach based on Bayesian inference, we attempt to quantify the probability of obtaining the observed distribution of values given a null model in which developmental constraint is absent. Since this probability is in the region of 10(-20), we conclude that constraint must be involved. We discuss various implications of this conclusion, and comment on the unexpected absence of neoteny and progenesis in centipede evolution. Copyright 1999 Academic Press.

Journal Article↗

On the probability model for asthma attacks.

In environmental epidemiology, the impact of environmental agents on symptoms or health status is of interest. This influence is described quantitatively in the theory of Whittemore & Keller (1979). They formulated a logistic model for individuals that is useful in evaluation of panel studies in which each participant protocols whether he does or does not have a certain symptom each day. In the present paper an equation for the prevalence of symptoms in the study population that is defined as the fraction of symptomatic subjects is deduced from the model for individuals. The model for the aggregated quantity depends on the individuals' parameters in a nonlinear manner. The relationship between the individual-based model and the corresponding population-based model is illustrated by means of a simulated panel. Bayesian estimates of the parameters are calculated and compared for both approaches. Bayesian inference enables to apply the prevalence model to a population of non-identical individuals. For such a heterogeneous population, we observe an attenuation of environmental effects on the aggregated symptom prevalence in comparison to the individual-based approach. The presented theory is applicable not only to panel studies but also in time-series analysis of prevalences and incidences.

Asthma↗

Bayesian estimation of dynamical systems: an application to fMRI.

This paper presents a method for estimating the conditional or posterior distribution of the parameters of deterministic dynamical systems. The procedure conforms to an EM implementation of a Gauss-Newton search for the maximum of the conditional or posterior density. The inclusion of priors in the estimation procedure ensures robust and rapid convergence and the resulting conditional densities enable Bayesian inference about the model parameters. The method is demonstrated using an input-state-output model of the hemodynamic coupling between experimentally designed causes or factors in fMRI studies and the ensuing BOLD response. This example represents a generalization of current fMRI analysis models that accommodates nonlinearities and in which the parameters have an explicit physical interpretation. Second, the approach extends classical inference, based on the likelihood of the data given a null hypothesis about the parameters, to more plausible inferences about the parameters of the model given the data. This inference provides for confidence intervals based on the conditional density.

Bayes Theorem↗

Efficient kernel density estimation of shape and intensity priors for level set segmentation.

We propose a nonlinear statistical shape model for level set segmentation which can be efficiently implemented. Given a set of training shapes, we perform a kernel density estimation in the low dimensional subspace spanned by the training shapes. In this way, we are able to combine an accurate model of the statistical shape distribution with efficient optimization in a finite-dimensional subspace. In a Bayesian inference framework, we integrate the nonlinear shape model with a nonparametric intensity model and a set of pose parameters which are estimated in a more direct data-driven manner than in previously proposed level set methods. Quantitative results show superior performance (regarding runtime and segmentation accuracy) of the proposed nonparametric shape prior over existing approaches.

Algorithms↗

A Bayesian approach to Weibull survival models--application to a cancer clinical trial.

In this paper we outline a class of fully parametric proportional hazards models, in which the baseline hazard is assumed to be a power transform of the time scale, corresponding to assuming that survival times follow a Weibull distribution. Such a class of models allows for the possibility of time varying hazard rates, but assumes a constant hazard ratio. We outline how Bayesian inference proceeds for such a class of models using asymptotic approximations which require only the ability to maximize the joint log posterior density. We apply these models to a clinical trial to assess the efficacy of neutron therapy compared to conventional treatment for patients with tumours of the pelvic region. In this trial there was prior information about the log hazard ratio both in terms of elicited clinical beliefs and the results of previous studies. Finally, we consider a number of extensions to this class of models, in particular the use of alternative baseline functions, and the extension to multi-state data.

Bayes Theorem↗

Probability and the patient state space.

This paper describes work to develop a model-based system to support clinical decision-making. In previous articles, we have developed (from 695 measurement sets obtained from 148 patients) a physiologic state classification based on a set of 11 cardiovascular and metabolic measurements. There is an R or reference state, for stable ICU patients. Patients under (operative, traumatic, or compensated septic) stress, or with (septic or hepatic) metabolic, respiratory, or cardiac insufficiency are in the A, B, C, or D states, respectively. We wished to make the state easier to measure and eventually available continuously, automatically, and noninvasively, as well as reflecting a wider group of bodily systems. The 5 centers define a 4 dimensional affine subspace, designated the cardiovascular state space. Using eigenvector analysis, we have found four new derived physiologic variables CV1, CV2, CV3, and CV4 that span the state space. We have fit sets of linear regression equations that allow the patient's position in the state space, and therefore his state, to be determined from more easily obtainable sets of measurements. Further, we selected 1966 measurement sets from 512 patients at two hospitals. We used the data from 250 of these patients to define 13 prototypical types, namely survivors and deaths from various combinations of sepsis, cardiogenic decompensation, cirrhosis, and pneumonitis, following trauma or general surgery. For any future patient, the statistical theory of Bayesian inference allows one to infer back from the measurements observed to the probability of his being of any of these types and of surviving or dying. We used this method to predict the outcome of the other 262 patients, prospectively. Statistically, the predictions of survival or death were not significantly different from the actual. For individual patients, the method predicts a clinical course that closely follows the actual episodes in their history. These results confirm and explain the validity of the concept of the patient state and make the state easier to compute. The patient state and the probability plot together help to stage, select, and evaluate therapy. They do not replace the clinician's judgement, but rather are tools that help the clinician to exercise judgement.

Adult↗

Extensive gene flow blurs phylogeographic but not phylogenetic signal in Olea europaea L.

Genetic structure and evolutionary patterns of the wild olive tree (Olea europaea L.) were investigated with AFLP fingerprinting data at three geographic levels: (a) phylogenetic relationships of the six currently recognized subspecies in Eurasia and Africa; (b) lineage identification in subsp. europaea of the Mediterranean basin; and (c) phylogeography in the western Mediterranean. Two statistical approaches (Bayesian inference and analysis of molecular variance) were used to analyse the AFLP fingerprints. To determine the congruency and transferability of results across studies previous RAPD and ISSR data were analysed in a similar manner. Comparisons proved that qualitative results were mostly congruent but quantitative values differed, depending on the method of analysis. Neighbour-Joining analysis of AFLP phenotypes supported current classification of subspecies. At a Mediterranean scale no clear cut phylogeographic pattern was recovered, likely due to extensive gene flow between populations of subsp. europaea. Gene flow estimates calculated with conventional F-statistics showed that reproductive barriers separated neither populations nor lineages of O. europaea. Genetic divergence between eastern and western parts of the Mediterranean basin was observed only when geographical and population information were incorporated into the analyses through hierarchical analysis of molecular variance (AMOVA). Within the western Mediterranean, the highest genetic diversity was found in two regions: on both sides of the Strait of Gibraltar and in the Balearic archipelago. Additionally, long-lasting isolation of the northern-most populations of the Iberian Peninsula appeared to be responsible for a significant divergence.

DNA Fingerprinting↗

Phylogeny of symbiotic cyanobacteria within the genus Nostoc based on 16S rDNA sequence analyses.

A phylogenetic analysis of selected symbiotic Nostoc strain sequences and available database 16S rDNA sequences of both symbiotic and free-living cyanobacteria was carried out using maximum likelihood and Bayesian inference techniques. Most of the symbiotic strains fell into well separated clades. One clade consisted of a mixture of symbiotic and free-living isolates. This clade includes Nostoc sp. strain PCC 73102, the reference strain proposed for Nostoc punctiforme. A separate symbiotic clade with isolates exclusively from Gunnera species was also obtained, suggesting that not all symbiotic Nostoc species can be assigned to N. punctiforme. Moreover, isolates from Azolla filiculoides and one from Gunnera dentata were well nested within a clade comprising most of the Anabaena sequences. This result supports the affiliation of the Azolla isolates with the genus Anabaena and shows that strains within this genus can form symbioses with additional hosts. Furthermore, these symbiotic strains produced hormogonia, thereby verifying that hormogonia formation is not absent in Anabaena and cannot be used as a criterion to distinguish it from Nostoc.

DNA, Bacterial↗