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PubMed2005

The use of quantitative oculometry in the assessment of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterised by progressive motor, cognitive and psychiatric symptoms. Objective measurement of disease severity is of increasing importance for detecting symptomatic disease, as well as monitoring disease progression and the response to novel therapeutic interventions. Using a newly-developed infra-red scleral oculometer, we measured saccadic latencies and durations in HD patients exhibiting a broad range of symptoms (n=24) and control subjects of comparable ages (n=20) to see whether these parameters might reflect the presence or severity of HD. Latency distributions were characterised by creating reciprobit plots for each subject, whilst parametric statistics were applied to durations. Compared with the control group, we found the HD group had a significantly increased median latency, and early saccades were more prominent. In addition, HD patients exhibited an increased saccadic duration and variability of duration. Using Bayesian (likelihood) analysis, we obtained saccadic support values for the presence of clinical HD, which correlated with the motor Unified Huntington's Disease Rating Scale (UHDRS) score in these patients. A sensitivity/specificity analysis of all 44 participants showed that the use of this multivariate support measure was highly successful in predicting HD status, correctly diagnosing 75% of the HD patients, and (95%) of the controls; with a different criterion, these figures were 96 and 15%. Furthermore, we correctly predicted absence of disease in two additional subjects subsequently confirmed to be genetically unaffected. This strongly suggests that multivariate support values derived from saccadic parameters may provide an objective, quantitative biomarker of HD, especially the degree of motor impairment. However, larger longitudinal studies are required to determine whether they can reliably detect the earliest presymptomatic disease, or faithfully reflect disease progression.

Adult↗
PubMed2005

Fungi evolution revisited: application of the penalized likelihood method to a Bayesian fungal phylogeny provides a new perspective on phylogenetic relationships and divergence dates of Ascomycota groups.

The depiction of evolutionary relationships within phylum Ascomycota is still controversial because of unresolved branching orders in the radiation of major taxa. Here we generated a dataset of 166 small subunit (18S) rDNA sequences, representative of all groups of Fungi and used as input in a Bayesian phylogenetic analysis. This phylogeny suggests that Discomycetes are a basal group of filamentous Ascomycetes and probably maintain ancestor characters since their representatives are intermingled among other filamentous fungi. Also, we show that the evolutionary rate heterogeneity within Ascomycota precludes the assumption of a global molecular clock. Accordingly, we used the penalized likelihood method, and for calibration we included a 400 million-year-old Pyrenomycete fossil considering two distinct scenarios found in the literature, one with an estimated date of 1576 Myr for the plant-animal-fungus split and the other with an estimated date of 965 Myr for the animal-fungus split. Our data show that the current classification of the fossil as a Pyrenomycete is not compatible with the second scenario. Estimates under the first scenario are older than dates proposed in previous studies based on small subunit rDNA sequences but support estimates based on multiprotein analysis, suggesting that the radiation of the major Ascomycota groups occurred into the Proterozoic era.

Ascomycota↗
PubMed2005

Genomic inventory and expression of Sox and Fox genes in the cnidarian Nematostella vectensis.

The Sox and Forkhead (Fox) gene families are comprised of transcription factors that play important roles in a variety of developmental processes, including germ layer specification, gastrulation, cell fate determination, and morphogenesis. Both the Sox and Fox gene families are divided into subgroups based on the amino acid sequence of their respective DNA-binding domains, the high-mobility group (HMG) box (Sox genes) or Forkhead domain (Fox genes). Utilizing the draft genome sequence of the cnidarian Nematostella vectensis, we examined the genomic complement of Sox and Fox genes in this organism to gain insight into the nature of these gene families in a basal metazoan. We identified 14 Sox genes and 15 Fox genes in Nematostella and conducted a Bayesian phylogenetic analysis comparing HMG box and Forkhead domain sequences from Nematostella with diverse taxa. We found that the majority of bilaterian Sox groups have clear Nematostella orthologs, while only a minority of Fox groups are represented, suggesting that the evolutionary pressures driving the diversification of these gene families may be distinct from one another. In addition, we examined the expression of a subset of these genes during development in Nematostella and found that some of these genes are expressed in patterns consistent with roles in germ layer specification and the regulation of cellular behaviors important for gastrulation. The diversity of expression patterns among members of these gene families in Nematostella reinforces the notion that despite their relatively simple morphology, cnidarians possess much of the molecular complexity observed in bilaterian taxa.

Amino Acid Sequence↗
PubMed2026

Cell-type-specific genetic associations in Lewy body dementia identified using single-cell eQTL-based Mendelian randomization.

BACKGROUND: Lewy body dementia (LBD) is a complex neurodegenerative disorder marked by α-synuclein aggregation and dual impairment of cognitive and motor function.While genome-wide association studies have identified risk loci, the cellular mechanisms linking genetic variation to disease susceptibility remain largely unexplored. METHODS: We performed single-cell transcriptome-wide Mendelian randomization using brain cell-type-specific eQTLs across eight major cell types. Genetic associations were evaluated using inverse-variance weighted models, followed by Bayesian colocalization analysis. Replication was performed in independent stratified LBD cohorts based on APOE ε4 carrier status. Phenome-wide association analysis was included as a supplementary, descriptive assessment of cross-trait associations. RESULTS: Expression of ANKRD65 in excitatory neurons was significantly associated with reduced LBD risk (odds ratio = 0.65, 95 % CI: 0.52-0.81, p = 0.00013). This association passed a false discovery rate of 0.1 and showed strong evidence of colocalization (posterior probability = 0.93). Effect direction was consistent across APOE ε4+ and ε4- LBD subgroups in independent cohorts. No genome-wide significant associations were observed with non-neurological traits in the phenome-wide analysis. CONCLUSIONS: Our findings identify a genetically supported, cell-type-resolved association between ANKRD65 expression in excitatory neurons and LBD risk. This study demonstrates the value of integrating cell-resolved transcriptomic regulation with genetic inference to pinpoint functionally relevant targets in neurodegenerative diseases.

Humans↗
PubMed2006

New developments in exposure assessment: the impact on the practice of health risk assessment and epidemiological studies.

The field of exposure assessment has matured significantly over the past 10-15 years. Dozens of studies have measured the concentrations of numerous chemicals in many media to which humans are exposed. Others have catalogued the various exposure pathways and identified typical values which can be used in the exposure calculations for the general population such as amount of water or soil ingested per day or the percent of a chemical than can pass through the skin. In addition, studies of the duration of exposure for many tasks (e.g. showering, jogging, working in the office) have been conducted which allow for more general descriptions of the likely range of exposures. All of this information, as well as the development of new and better models (e.g. air dispersion or groundwater models), allow for better estimates of exposure. In addition to identifying better exposure factors, and better mathematical models for predicting the aerial distribution of chemicals, the conduct of simulation studies and dose-reconstruction studies can offer extraordinary opportunities for filling in data gaps regarding historical exposures which are critical to improving the power of epidemiology studies. The use of probabilistic techniques such as Monte Carlo analysis and Bayesian statistics have revolutionized the practice of exposure assessment and has greatly enhanced the quality of the risk characterization. Lastly, the field of epidemiology is about to undergo a sea change with respect to the exposure component because each year better environmental and exposure models, statistical techniques and new biological monitoring techniques are being introduced. This paper reviews these techniques and discusses where additional research is likely to pay a significant dividend. Exposure assessment techniques are now available which can significantly improve the quality of epidemiology and health risk assessment studies and vastly improve their usefulness. As more quantitative exposure components can now be incorporated into these studies, they can be better used to identify safe levels of exposure using customary risk assessment methodologies. Examples are drawn from both environmental and occupational studies illustrating how these techniques have been used to better understand exposure to specific chemicals. Some thoughts are also presented on what lessons have been learned about conducting exposure assessment for health risk assessments and epidemiological studies.

Bayes Theorem↗
PubMed2006

Using Bayesian statistics to estimate the coefficients of a two- component second-order chlorine bulk decay model for a water distribution system.

Most chlorine decay models for the bulk phase in a water distribution system consider only chlorine concentration and time. Clark [1998. Chlorine demand and trihalomethane formation kinetics: a second-order model. J. Environ. Eng. 124(1), 16-24] first proposed a two-component second-order chlorine decay model based on the concept of competing reacting substances. A corrected mathematical formulation is developed and, because the recent findings suggested that not all natural organic matter (NOM) is involved in the chlorine decay process, an additional parameter is introduced. A parameter assignment method employing Bayesian statistical analysis incorporating Monte Carlo Markov chain (MCMC) with Gibbs sampling to make inferences, is employed in the estimation of model parameters. Three parameters are estimated for the model, namely the ratio of chlorine to TOC, the chlorine reaction rate, and a fraction factor of TOC which represents the true amount of TOC involved in chlorine decay process. Water samples taken from Goderich in the summer of 2005, are used for estimating the parameters.

Bayes Theorem↗
PubMed2005

Characterization of a cetacean aromatase (CYP19) and the phylogeny and functional conservation of vertebrate aromatase.

Aromatase (cytochrome P450 19, CYP19, P450arom) is the enzyme responsible for the production of estrogens, hormones critical for development and reproduction. Aromatase was sequenced from a white-sided dolphin (Lagenorhynchus acutus) ovary, transiently transfected into HEK 293 cells, and the expressed protein was characterized for aromatase activity in the presence of androstenedione and testosterone and after exposure to the aromatase inhibitor letrazole. The Kms for androstenedione and testosterone were 63.5 and 75 nM, respectively, values that are very similar to those reported for other mammalian aromatases. A Bayesian phylogenetic analysis of the vertebrate aromatases was performed on the amino acid sequences of aromatases from fish, amphibians, reptiles, birds, and mammals. Based on known species phylogeny, the cetacean aromatase showed an expected grouping with artiodactyls (cow, sheep, and goat). An analysis of functional divergence showed strong conservation of aromatase across the entire protein, which indicates that the observed sequence divergence is functionally neutral.

Animals↗
PubMed2001

Temperature dependence of the folding and unfolding kinetics of the GCN4 leucine zipper via 13C(alpha)-NMR.

Studies by one-dimensional NMR are reported on the interconversion of folded and unfolded forms of the GCN4 leucine zipper in neutral saline buffer. The peptide bears 99% 13C(alpha) labels at three sites: V9, L12, and G31. Time-domain 13C(alpha)-NMR spectra are interpreted by global Bayesian lineshape analysis to extract the rate constants for both unfolding and folding as functions of temperature in the range 47-71 degrees C. The data are well fit by the assumption that the same rate constants apply at each labeled site, confirming that only two conformational states need be considered. Results show that 1) both processes require a free energy of activation; 2) unfolding is kinetically enthalpy-opposed and entropy-driven, while folding is the opposite; and 3) the transition state dimer ensemble averages approximately 40% helical. The activation parameters for unfolding, derived from NMR data at the elevated temperatures where both conformations are populated, lead to estimates of the rate constant at low temperatures (5-15 degrees C) that agree with extant values determined by stopped-flow CD via dilution from denaturing media. However, the corresponding estimated values for the folding rate constant are larger by two to three orders of magnitude than those obtained by stopped flow. We propose that this apparent disagreement is caused by the necessity, in the stopped-flow experiment, for initiation of new helices as the highly denaturant-unfolded molecule adjusts to the newly created benign solvent conditions. This must reduce the success rate of collisions in producing the folded molecule. In the NMR determinations, however, the unfolded chains always have a small, but essential, helix content that makes such initiation unnecessary. Support for this hypothesis is adduced from recent extant experiments on the helix-coil transition in single-chain helical peptides and from demonstration that the folding rate constants for coiled coils, as obtained by stopped flow, are influenced by the nature of the denaturant used.

Amino Acid Sequence↗
PubMed2002

A comparison of rate-response toxicity tests with Aphidius rhopalosiphi (Hymenoptera: Aphidiidae) using glass, leaves and whole plants as substrate.

Rate-response toxicity tests on Aphidius rhopalosiphi were carried out with seven plant protection products using three different test systems. The first type of test system conformed to the standard laboratory testing guidelines and consisted of two treated glass plates fitted into a metal frame, which created an enclosure for the wasps. In the second type of test system, the plant protection products were applied to two bean-leaf disks mounted on agar filled dishes, which were fitted to a transparent plastic frame. The third type of test system consisted of potted barley plants, which were treated and covered with an acrylic cylinder. Adult wasps were exposed to the dried residues of the products for 48 h before wasp mortality was assessed. For each product and test system, the LR50 value (application rate at which 50% mortality of the wasps occurs) was determined with a Bayesian Probit analysis. Technically, rate-response testing was feasible with all three test systems, and rate-response relationships could be established. The results support a sequential testing scheme, as the LR50 values increased from 'glass plate test' to 'excised leaf test' to 'whole plant test' with all tested products. The LR50 values were 7.8-340 times higher on whole plants than on glass plates. Because of the variability of this factor, a numerical safety factor cannot be used to substitute extended laboratory testing for regulatory purposes.

Animals↗
PubMedDate not supplied

Pharmacokinetic-pharmacodynamic modeling: why?

At present, pharmacokinetic-pharmacodynamic (PK-PD) modeling has emerged as a major tool in clinical pharmacology to optimize drug use by designing rational dosage forms and dosage regimes. Quantitative representation of the dose-concentration-response relationship should provide information for prediction of the level of response to a certain level of drug dose. Several mathematical approaches can be used to describe such relationships, depending on the single dose or the steady-state measurements carried out. With concentration and response data on-phase, basic models such as fixed-effect, linear, log-linear, E(MAX), and sigmoid E(MAX) can be sufficient. However, time-variant pharmacodynamic models (effect compartment, acute tolerance, sensitization, and indirect responses) can be required when kinetics and response are out-of-phase. To date, methodologies available for PK-PD analysis barely suppose the use of powerful computing resources. Some of these algorithms are able to generate individual estimates of parameters based on population analysis and Bayesian forecasting. Notwithstanding, attention must be paid to avoid overinterpreted data from mathematical models, so that reliability and clinical significance of estimated parameters will be valuable when underlying physiologic processes (disease, age, gender, etc.) are considered.

Algorithms↗
PubMed2001

An elementary introduction to Bayesian computing using WinBUGS.

Bayesian statistics provides effective techniques for analyzing data and translating the results to inform decision making. This paper provides an elementary tutorial overview of the WinBUGS software for performing Bayesian statistical analysis. Background information on the computational methods used by the software is provided. Two examples drawn from the field of medical decision making are presented to illustrate the features and functionality of the software.

Bayes Theorem↗
PubMed2004

The phylogeny of Porinaceae (Ostropomycetidae) suggests a neotenic origin of perithecia in Lecanoromycetes.

The family Porinaceae (Trichotheliales) is characterized by perithecial ascomata of ascohymenial origin. The phylogenetic position of this family in the system of ascomycetes has been uncertain and is investigated using mtSSU rDNA sequences. The dataset consists of lichenized representatives of major ascomycete lineages, including those that were previously suspected as relatives of Porinaceae, such as Pyrenulaceae. The dataset was subjected to a Bayesian phylogenetic analysis implementing a Metropolis Coupled Markov Chain Monte Carlo method. The analysis confirms previous classification of the apothecial Gomphillaceae near to Graphidaceae, and suggests that the pyrenocarpous Porinaceae are also close to Graphidaceae, Gyalectaceae, and Stictidaceae. The subclass Ostropomycetidae is here suggested to include the families Gomphillaceae, Gyalectaceae, Graphidaceae (incl. Thelotremataceae), Porinaceae, and Stictidaceae. A special type of hemiangiocarpous ontogeny of the ascomata is shared throughout the Ostropomycetidae, and the closed fruit bodies of Porinaceae are apparently a result of a neotenic ontogeny. This is associated with special hymenial characters: rather thin-walled narrow asci, and a different consistency of the hymenial gels.

Ascomycota↗
PubMed2006

Solvation dynamics of the electron produced by two-photon ionization of liquid polyols. 1. Ethylene glycol.

Solvated electrons have been produced in ethylene glycol by two-photon ionization of the solvent with 263 nm femtosecond laser pulses. The two-photon absorption coefficient of ethylene glycol at 263 nm is determined to be beta = (2.1 +/- 0.2) x 10(-11) m W(-1). The dynamics of electron solvation in ethylene glycol has been studied by pump-probe transient absorption spectroscopy. So, time-resolved absorption spectra ranging from 430 to 710 nm have been measured. A blue shift of the spectra is observed for the first tens of picoseconds. Using the Bayesian data analysis method, the observed solvation dynamics are reconstructed with different models: stepwise mechanisms, continuous relaxation models, or combinations of stepwise and continuous relaxation. Comparison between models is in favor of continuous relaxation, which is mainly governed by solvent molecular motions.

Journal Article↗
PubMed2001

Gentamicin pharmacokinetics in preterm infants with a patent and a closed ductus arteriosus.

BACKGROUND AND AIM: A patent ductus arteriosus (PDA) may influence renal and hepatic blood flow and hence pharmacokinetics of drugs in neonates compared to neonates with a closed ductus arteriosus (CDA). A 10-percent difference of gentamicin pharmacokinetic parameters between PDA and CDA has been reported; but its implications are unclear. The relevance of this difference relative to the variability within the neonatal population was investigated. METHODS: Twenty-four neonates (12 with a PDA and 12 with a CDA) treated with gentamicin were retrospectively included. Before closing treatment of the PDA, serum levels were drawn and analysed for regular therapeutic drug monitoring of gentamicin. Data were analysed using the standard two-stage approach (STS) and an iterative 2-stage Bayesian population analysis approach (It2B). RESULTS: Both types of analysis showed no significant differences between both populations for gentamicin total body clearance per kg bodyweight (CL/kg). Volume of distribution per kg bodyweight (Vd/kg) tended to be larger and elimination rate (Kel) tended to be smaller in neonates with PDA. Multiple regression analysis showed for both populations highly significant correlations between total body clearance and body weight (p < 0.0001) or gestational age (p < 0.0001), and between volume of distribution and body weight (p < 0.0001) or gestational age (p < 0.0001). CONCLUSION: Although neonates with a PDA may have small differences in gentamicin pharmacokinetics compared to neonates with a CDA, this is not relevant for clinical practice taking the variability within that population into account.

Anti-Bacterial Agents↗
PubMed1997

Modeling of trough plasma bismuth concentrations.

Disposition pharmacokinetics of bismuth following oral dosing of ranitidine bismuth citrate are complicated and variable. An analysis of data from healthy volunteers suggests a model with three disposition compartments and first-order absorption. Patient data are pooled from 10 separate studies and consist of 1140 trough concentrations measured in 802 patients following dosing of 2 to 12 weeks duration. There are therefore insufficient data to obtain reliable parameter estimates for the full model and we use instead a much reduced model and an informative prior based on the volunteer data. Individual parameter estimates from this model can then be used to establish covariate relationships. Trough concentrations were influenced by the coadministration of clarithromycin and by creatinine clearance. A simulation study was carried out to check the validity of the estimates obtained from the reduced model. We carry out analysis via Bayesian sampling-based techniques. Throughout, we use predictive distributions for both diagnostic and inference purposes. In particular, we determine predicted distributions for the Cmax, Cmin and AUC characteristics of new individuals.

Bayes Theorem↗
PubMed2004

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations.

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.

Alleles↗
PubMed2005

A penalized maximum likelihood method for estimating epistatic effects of QTL.

Although epistasis is an important phenomenon in the genetics and evolution of complex traits, epistatic effects are hard to estimate. The main problem is due to the overparameterized epistatic genetic models. An epistatic genetic model should include potential pair-wise interaction effects of all loci. However, the model is saturated quickly as the number of loci increases. Therefore, a variable selection technique is usually considered to exclude those interactions with negligible effects. With such techniques, we may run a high risk of missing some important interaction effects by not fully exploring the extremely large parameter space of models. We develop a penalized maximum likelihood method. The method developed here adopts a penalty that depends on the values of the parameters. The penalized likelihood method allows spurious QTL effects to be shrunk towards zero, while QTL with large effects are estimated with virtually no shrinkage. A simulation study shows that the new method can handle a model with a number of effects 15 times larger than the sample size. Simulation studies also show that results of the penalized likelihood method are comparable to the Bayesian shrinkage analysis, but the computational speed of the penalized method is orders of magnitude faster.

Bayes Theorem↗