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Association between variants in the genes for adiponectin and its receptors with insulin resistance syndrome (IRS)-related phenotypes in Mexican Americans.

AIMS/HYPOTHESIS: The aim of this study was to examine whether genetic variation in ADIPOQ, ADIPOR1 and ADIPOR2 may contribute to increased susceptibility to components of the insulin resistance syndrome (IRS). MATERIALS AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) in ADIPOQ, ADIPOR1 and ADIPOR2 in Mexican American subjects (N=439) and performed an association analysis of IRS-related traits. RESULTS: Of the eight SNPs examined in the ADIPOQ gene, rs4632532 and rs182052 exhibited significant associations with BMI (p=0.029 and p=0.032), fasting specific insulin (p=0.023 and p=0.026), sum of skin folds (SS) (p=0.0089 and p=0.0084) and homeostasis model assessment of insulin sensitivity (HOMA-%S) (p=0.015 and p=0.016). Two other SNPs, rs266729 and rs2241767, were significantly associated with SS (p=0.036 and p=0.013). SNP rs7539542 of ADIPOR1 was significantly associated with BMI, SS and waist circumference (p=0.025, p=0.047 and p=0.0062). Fourteen of the ADIPOR2 SNPs were found to be significantly (p<0.05) associated with fasting plasma triglyceride concentrations. Four of these SNPs (rs10848569, rs929434, rs3809266 and rs12342) were in high pairwise linkage disequilibrium (r (2)=0.99) and were strongly associated with fasting triglyceride levels (p=0.00029, p=0.00016, p=0.00027 and p=0.00021). Adjusting for the effects of BMI and HOMA-%S on triglyceride concentrations increased significance to p=0.000060 for SNP rs929434. Bayesian quantitative trait nucleotide analysis was used to examine all possible models of gene action. Again, SNP rs929434 provided the strongest statistical evidence of an effect on triglyceride concentrations. CONCLUSIONS/INTERPRETATION: These results provide evidence for association of SNPs in ADIPOQ and its receptors with multiple IRS-related phenotypes. Specifically, several genetic variants in ADIPOR2 were strongly associated with decreased triglyceride levels.

Adiponectin↗

Biogeographic patterns and phylogeography of dwarf chameleons (Bradypodion) in an African biodiversity hotspot.

The southern African landscape appears to have experienced frequent shifts in vegetation associated with climatic change through the mid-Miocene and Plio-Pleistocene. One group whose historical biogeography may have been affected by these fluctuations are the dwarf chameleons (Bradypodion), due to their associations with distinct vegetation types. Thus, this group provides an opportunity to investigate historical biogeography in light of climatic fluctuations. A total of 138 dwarf chameleons from the Cape Floristic Region of South Africa were sequenced for two mitochondrial genes (ND2 and 16S), and resulting phylogenetic analyses showed two well-supported clades that are distributed allopatrically. Within clades, diversity among some lineages was low, and haplotype networks showed patterns of reticulate evolution and incomplete lineage sorting, suggesting relatively recent origins for some of these lineages. A dispersal-vicariance analysis and a relaxed Bayesian clock suggest that vicariance between the two main clades occurred in the mid-Miocene, and that both dispersal and vicariance have played a role in shaping present-day distributions. These analyses also suggest that the most recent series of lineage diversification events probably occurred within the last 3-6 million years. This suggests that the origins of many present-day lineages were founded in the Plio-Pleistocene, a time period that corresponds to the reduction of forests in the region and the establishment of the fynbos biome.

Animals↗

Comparison of phylogenetic metrics of transmission between symptomatic and asymptomatic tuberculosis in individuals who were incarcerated in Brazil in 2008-24: a retrospective genomic epidemiology study.

BACKGROUND: Tuberculosis control efforts have traditionally targeted symptomatic individuals; however, the role of asymptomatic cases in sustaining transmission is increasingly recognised. We aimed to quantify the contribution of asymptomatic tuberculosis to recent transmission using genomic and epidemiological data from a high-transmission setting. METHODS: We conducted a retrospective genomic epidemiology study of Mycobacterium tuberculosis isolates collected in Mato Grosso do Sul, Brazil, between Aug 25, 2008, and March 19, 2024. Available isolates underwent whole-genome sequencing. Demographic, clinical, incarceration history, and laboratory metadata were obtained from surveillance records. From Jan 1, 2017, to March 19, 2024, active case finding was conducted in the state's three largest prisons (all male-only facilities), during which sputum samples were collected from individuals irrespective of symptoms and tested using GeneXpert and culture. Comparisons of transmission between individuals with and without symptoms were restricted to individuals who were incarcerated and were identified through active case finding and for whom high-quality, M tuberculosis lineage 4 genomes were available. Metrics of recent transmission included phylogenetic clustering, time-scaled haplotype density (THD), local branching index (LBI), and transmission probabilities inferred using Bayesian Reconstruction and Evolutionary Analysis of Transmission Histories. FINDINGS: 4448 tuberculosis cases were notified in Mato Grosso do Sul in 2008-24. After excluding cases for which M tuberculosis isolates were not available or had low sequencing quality, who had contaminated cultures or mixed infection, or who were infected with non-lineage 4 M tuberculosis, we included 2362 lineage 4 M tuberculosis isolates with high-quality genome sequences. 1849 (78&#xb7;3%) of 2362 isolates were part of a genomic cluster. Among 2362 individuals with tuberculosis, 1137 (48&#xb7;1%) were incarcerated at diagnosis. Of these individuals, 505 were identified through active case finding in three male-only prisons. The median age was 30 years (IQR 25-37); 304 (60&#xb7;2%) had mixed ethnicity, 90 (17&#xb7;8%) were White, 56 (11&#xb7;1%) were Black, 13 (2&#xb7;6%) were Indigenous, and six (1&#xb7;2%) were Asian. 277 (54&#xb7;9%) had symptomatic disease and 228 (45&#xb7;1%) had asymptomatic tuberculosis. There were no significant differences between symptomatic and asymptomatic individuals in phylogenetic clustering (213 [76&#xb7;9%] of 277 vs 195 [85&#xb7;5%] of 228; p=0&#xb7;37), THD (median 0&#xb7;39 [IQR 0&#xb7;06-0&#xb7;62] vs 0&#xb7;50 [0&#xb7;09-0&#xb7;65]; p=0&#xb7;12), or LBI (0&#xb7;00863 [0&#xb7;00810-0&#xb7;00988] vs 0&#xb7;00871 [0&#xb7;00829-0&#xb7;01020]; p=0&#xb7;088). Bayesian transmission trees showed no significant difference in the number of secondary infections inferred from symptomatic compared with asymptomatic individuals (p=0&#xb7;56). These findings were consistent across genomic clusters and robust to model assumptions. INTERPRETATION: We identified no differences in transmission between individuals who were symptomatic and those who were asymptomatic using multiple genomic measures. In this high-transmission setting, where systematic screening is implemented, our findings indicate that asymptomatic tuberculosis substantially contributes to tuberculosis transmission at the population level. These results suggest that symptom-based case detection alone is likely to be insufficient to interrupt transmission and highlight the importance of expanded screening strategies in high-risk populations. FUNDING: US National Institutes of Health and the Brazilian National Research Council (CNPq).

Humans↗

Cost-benefit analysis of first-generation antihistamines in the treatment of allergic rhinitis.

BACKGROUND: The majority of individuals with allergic rhinitis in the US take first-generation antihistamines (FGAs). Although FGAs have been proven effective in alleviating allergic rhinitis symptoms, they have been associated with an increased risk of motor vehicle, aviation and occupational injuries and deaths, reduced productivity and impaired learning. OBJECTIVE: The objective of this analysis was to quantify the total costs and benefits of FGA use in the US from the societal perspective. METHODS: We used a decision-analytic model to quantify the annual societal costs and benefits of treatment with FGAs compared with the hypothetical alternative of no treatment for the population of individuals with allergic rhinitis and taking FGAs in the US in 2001. The benefit associated with FGA use was estimated using the willingness-to-pay framework and projected to the US population using published estimates of the prevalence of allergic rhinitis. The costs of FGA-associated sedation included lost productivity and the direct and indirect cost of unintentional injuries (including motor vehicle, occupational, public and home injuries and fatalities). The incidence of injuries and fatalities associated with FGA use was estimated using the risk of injury attributable to the sedentary effects of FGAs in the allergic rhinitis population. To evaluate uncertainty in the model assumptions, a probabilistic sensitivity analysis was conducted using Bayesian second-order Monte Carlo simulation. Costs and benefits are expressed in 2001 US dollars, using a 3% discount rate. RESULTS: Based on current utilisation, the total societal benefit (95% credible interval) associated with the use of FGAs for the treatment of allergic rhinitis was US 7.7 billion dollars (US 1.3 billion dollars to US 21 billion dollars). The societal cost of purchasing FGAs was only US 697 million dollars. However, the societal cost of FGA-associated sedation was US 11.3 billion dollars (US 2.4 billion dollars to US 50.8 billion dollars). The annual societal net benefit of FGA use for the treatment of allergic rhinitis in the US was -US4.2 billion dollars (-US 36 billion dollars to +US 0.296 billion dollars). The net benefit was negative in 97% of the 10,000 Monte Carlo simulations. CONCLUSIONS: The societal benefits of FGA use in alleviating the symptoms of allergic rhinitis are significant. However, based on the assumptions, probability distributions and parameter estimate ranges used in the current model, it is very likely that the costs associated with sedation exceed the benefits of FGA use in the US. The cost of FGA-associated sedation is comparable to estimates of the cost of all medical care expenditures on respiratory conditions in the US (US 12.1 billion dollars to US 31.3 billion dollars) [1996 values] and provides compelling evidence of the economic burden of sedation associated with FGA use.

Accidents↗

Shared genetic architecture of obesity and gastroesophageal reflux disease.

Obesity is identified as a risk factor of gastroesophageal reflux disease (GERD). This study aims to elucidate the shared genetic architecture of obesity-related phenotypes and GERD. Based on the publicly available genome-wide association studies' datasets, this genome-wide pleiotropic association study was conducted with various genetic approaches (including linkage disequilibrium score regression, high-definition likelihood inference for genetic correlations, pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis) sequentially to unravel the genetic associations from single-nucleotide polymorphism to gene levels, and to reveal the underlying shared genetic architecture between obesity-related phenotypes and GERD. This study discovered shared genetic mechanisms between GERD and several obesity-related phenotypes, including arm fat percentage (left), arm fat percentage (right), leg fat percentage (left), leg fat percentage (right), trunk fat percentage, waist-to-hip ratio, and body mass index. Significant genetic correlations were observed by linkage disequilibrium score regression and high-definition likelihood inference for genetic correlations, with multiple associated pleiotropic loci and their mapped genes identified by pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation, Bayesian colocalization, summary-based Mendelian randomization, and multi-marker analysis of genomic annotation analysis. Additionally, several brain tissues were identified to be linked to both obesity and GERD by multi-marker analysis of genomic annotation. This research provided strong evidence of genetic correlations and brought novel insights into the underlying genetic connections and shared genetic architectures of obesity and GERD.

Humans↗

Network analysis of mild cognitive impairment.

We present a network analysis of a cross-sectional study of mild cognitive impairment (MCI). Network analysis, as opposed to univariate analysis, accounts for interactions among brain structures in explaining a clinical outcome. In this context, we analyze structural magnetic resonance (MR) data based on a Bayesian network representation of variables in the problem domain. The Bayesian network resulting from this analysis reveals complex, nonlinear multivariate associations among morphological changes in the left hippocampus and in the right thalamus and the presence of mild cognitive impairment. This Bayesian network could be used to predict the presence of mild cognitive impairment from structural MR scans.

Aged↗

A Bayesian approach for predicting judged hearing disability.

A method of determining the cutoff point for an administrative decision to award compensation is proposed. To construct the predictive system a Bayesian approach and discriminant analysis were employed. Judged hearing disability was used as the criterion with audiometric scores as the determining variables. The common law doctrine of the balance of probability was used as the criterion, namely the 50th centile, on which to propose a cutoff point. The highest precision in predicting judged hearing disability was obtained with an average audiometric score at 1,000, 2,000, 3,000, 4,000 Hz in the worse ear. Assuming that judged hearing disability is a valid predictor of handicap, the cutoff point based on the balance of probability (50th centile) was obtained at 25 dB. The study also confirmed results from previous studies: hearing sensitivity in frequencies higher than 2,000 Hz is required to predict hearing disability and handicap, judged hearing disability is better correlated with hearing sensitivity in the worst ear, and the audiometric cutoff point for a medical legal definition of impairment should be lower than what certain technical groups have proposed in the past.

Audiometry↗

Classical and Bayesian inference in neuroimaging: applications.

In Friston et al. ((2002) Neuroimage 16: 465-483) we introduced empirical Bayes as a potentially useful way to estimate and make inferences about effects in hierarchical models. In this paper we present a series of models that exemplify the diversity of problems that can be addressed within this framework. In hierarchical linear observation models, both classical and empirical Bayesian approaches can be framed in terms of covariance component estimation (e.g., variance partitioning). To illustrate the use of the expectation-maximization (EM) algorithm in covariance component estimation we focus first on two important problems in fMRI: nonsphericity induced by (i) serial or temporal correlations among errors and (ii) variance components caused by the hierarchical nature of multisubject studies. In hierarchical observation models, variance components at higher levels can be used as constraints on the parameter estimates of lower levels. This enables the use of parametric empirical Bayesian (PEB) estimators, as distinct from classical maximum likelihood (ML) estimates. We develop this distinction to address: (i) The difference between response estimates based on ML and the conditional means from a Bayesian approach and the implications for estimates of intersubject variability. (ii) The relationship between fixed- and random-effect analyses. (iii) The specificity and sensitivity of Bayesian inference and, finally, (iv) the relative importance of the number of scans and subjects. The forgoing is concerned with within- and between-subject variability in multisubject hierarchical fMRI studies. In the second half of this paper we turn to Bayesian inference at the first (within-voxel) level, using PET data to show how priors can be derived from the (between-voxel) distribution of activations over the brain. This application uses exactly the same ideas and formalism but, in this instance, the second level is provided by observations over voxels as opposed to subjects. The ensuing posterior probability maps (PPMs) have enhanced anatomical precision and greater face validity, in relation to underlying anatomy. Furthermore, in comparison to conventional SPMs they are not confounded by the multiple comparison problem that, in a classical context, dictates high thresholds and low sensitivity. We conclude with some general comments on Bayesian approaches to image analysis and on some unresolved issues.

Algorithms↗

Armenian Y chromosome haplotypes reveal strong regional structure within a single ethno-national group.

Armenia has been little-studied genetically, even though it is situated in an important area with respect to theories of ancient Middle Eastern population expansion and the spread of Indo-European languages. We screened 734 Armenian males for 11 biallelic and 6 microsatellite Y chromosome markers, segregated them according to paternal grandparental region of birth within or close to Armenia, and compared them with data from other population samples. We found significant regional stratification, on a level greater than that found in some comparisons between different ethno-national identities. A diasporan Armenian sub-sample (collected in London) was not sufficient to describe this stratified haplotype distribution adequately, warning against the use of such samples as surrogates for the non-diasporan population in future studies. The haplotype distribution and pattern of genetic distances suggest a high degree of genetic isolation in the mountainous southern and eastern regions, while in the northern, central and western regions there has been greater admixture with populations from neighbouring Middle Eastern countries. Georgia, to the north of Armenia, also appears genetically more distinct, suggesting that in the past Trans-Caucasia may have acted as a genetic barrier. A Bayesian full-likelihood analysis of the Armenian sample yields a mean estimate for the start of population growth of 4.8 thousand years ago (95% credible interval: 2.0-11.1), consistent with the onset of Neolithic farming. The more isolated southern and eastern regions have high frequencies of a microsatellite defined cluster within haplogroup 1 that is centred on a modal haplotype one step removed from the Atlantic Modal Haplotype, the centre of a cluster found at high frequencies in England, Friesland and Atlantic populations, and which may represent a remnant paternal signal of a Paleolithic migration event.

Armenia↗

Practical problems in interim analyses, with particular regard to estimation.

This article considers some of the practical problems inherent in interim analyses and stopping rules for randomized clinical trials. Topics covered include group sequential designs, trials with unplanned interim analyses, estimation problems in clinical trials with planned interim analyses, and the balance between individual and collective ethics. Particular attention is paid to the fact that clinical trials that stop early are prone to exaggerate the magnitude of treatment effect. Accordingly, a Bayesian "shrinkage" method of analysis is proposed to help quantify the extent to which surprisingly large point and interval estimates of treatment difference in clinical trials that stop early should be moderated.

Bayes Theorem↗

Probabilistic representation of the exposure of consumers to Clostridium botulinum neurotoxin in a minimally processed potato product.

We have examined the potential of a well-specified, minimally processed potato product as a vehicle for the exposure of consumers to Clostridium botulinum neurotoxin. The product is a relatively simple combination of raw potato flakes, flour, starch and other minor ingredients and has an extended lifetime under refrigeration conditions. A combination of information and data, from a variety of sources that includes the manufacturer, has shown that the product is particularly safe with respect to non-proteolytic C. botulinum hazards. The model concentrates on a simple end point, the toxicity of an individual retail unit of the product at the point of consumer preparation, which is related to an individual risk. The probabilistic analysis was built using Bayesian Belief Network (BBN) techniques.

Bayes Theorem↗

Comparison of recent methods for inference of variable influence in neural networks.

Neural networks (NNs) belong to 'black box' models and therefore 'suffer' from interpretation difficulties. Four recent methods inferring variable influence in NNs are compared in this paper. The methods assist the interpretation task during different phases of the modeling procedure. They belong to information theory (ITSS), the Bayesian framework (ARD), the analysis of the network's weights (GIM), and the sequential omission of the variables (SZW). The comparison is based upon artificial and real data sets of differing size, complexity and noise level. The influence of the neural network's size has also been considered. The results provide useful information about the agreement between the methods under different conditions. Generally, SZW and GIM differ from ARD regarding the variable influence, although applied to NNs with similar modeling accuracy, even when larger data sets sizes are used. ITSS produces similar results to SZW and GIM, although suffering more from the 'curse of dimensionality'.

Algorithms↗

Phylogeny and evolution of the Australo-Papuan honeyeaters (Passeriformes, Meliphagidae).

We analyzed nucleotide variation at four loci for 75 species to produce a phylogenetic hypothesis for the Meliphagidae, and to examine the evolution and biogeographic history of the Meliphagidae. Both maximum parsimony and Bayesian methods of phylogenetic analysis were employed. The family was found to be monophyletic, though the genera Certhionyx, Anthochaera, and Phylidonyris were not. Four major clades were recovered and the spinebills (Acanthorhynchus) formed the sister clade to the remainder of the family in most analyses. The Australian endemic arid-adapted chats (Epthianura, Ashbyia) were found to be nested deeply within the family Meliphagidae. No evidence was found to support the hypothesis of separate New Guinean and Australian endemic radiations, nor of a close phylogenetic relationship between taxa from the New Guinea highlands and those from Australian northern rainforests.

Animals↗

Phylogeny of Coreopsideae (Asteraceae) using ITS sequences suggests lability in reproductive characters.

Relationships among the 21 genera within the tribe Coreopsideae (Asteraceae) remain poorly resolved despite phylogenetic studies using morphological and anatomical traits. Recent molecular phylogenies have also indicated that some Coreopsideae genera are not monophyletic. We used internal transcribed spacer (ITS) sequences from representatives of 19 genera, as well as all major lineages in those genera that are not monophyletic, to examine phylogenetic relationships within this group. To examine the affects of alignment and method of analysis on our conclusions, we obtained alignments using five different parameters and analyzed all five alignments with distance, parsimony, and Bayesian methods. The method of analysis had a larger impact on relationships than did alignments, although different analytical methods gave very similar results. Although not all relationships could be resolved, a number of well-supported lineages were found, some in conflict with earlier hypotheses. We did not find monophyly in Bidens, Coreopsis, and Coreocarpus, though other genera were monophyletic for the taxa we included. Morphological and anatomical traits which have been used previously to resolve phylogenetic relationships in this group were mapped onto the well-supported nodes of the ITS phylogeny. This analysis indicated that floral and fruit characters, which have been used extensively in phylogenetic studies in the Coreopsideae, show a higher degree of evolutionary lability in this group than the more highly conserved vegetative and photosynthetic traits.

Asteraceae↗

Properties of phylogenetic trees generated by Yule-type speciation models.

We investigate some discrete structural properties of evolutionary trees generated under simple null models of speciation, such as the Yule model. These models have been used as priors in Bayesian approaches to phylogenetic analysis, and also to test hypotheses concerning the speciation process. In this paper we describe new results for three properties of trees generated under such models. Firstly, for a rooted tree generated by the Yule model we describe the probability distribution on the depth (number of edges from the root) of the most recent common ancestor of a random subset of k species. Next we show that, for trees generated under the Yule model, the approximate position of the root can be estimated from the associated unrooted tree, even for trees with a large number of leaves. Finally, we analyse a biologically motivated extension of the Yule model and describe its distribution on tree shapes when speciation occurs in rapid bursts.

Animals↗

Applications of population approaches in toxicology.

Many experimental or observational studies in toxicology are best analysed in a population framework. Recent examples include investigations of the extent and origin of intra-individual variability in toxicity studies, incorporation of genotypic information to address intra-individual variability, optimal design of experiments, and extension of toxicokinetic modelling to the analysis of biomarker studies. Bayesian statistics provide powerful numerical methods for fitting population models, particularly when complex mechanistic models are involved. Challenges and limitations to the use of population models, in terms of basic structure, computational burden, ease of implementation and data accessibility, are identified and discussed.

Animals↗

Evaluation of scientific evidence using Bayesian networks.

Bayesian networks provide a valuable aid for representing epistemic relationships in a body of uncertain evidence. The paper proposes some simple Bayesian networks for standard analysis of patterns of inference concerning scientific evidence, with a discussion of the rationale behind the nets, the corresponding probabilistic formulas, and the required probability assessments.

Adult↗