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PubMed2005

Biochemical networks with uncertain parameters.

The modelling of biochemical networks becomes delicate if kinetic parameters are varying, uncertain or unknown. Facing this situation, we quantify uncertain knowledge or beliefs about parameters by probability distributions. We show how parameter distributions can be used to infer probabilistic statements about dynamic network properties, such as steady-state fluxes and concentrations, signal characteristics or control coefficients. The parameter distributions can also serve as priors in Bayesian statistical analysis. We propose a graphical scheme, the 'dependence graph', to bring out known dependencies between parameters, for instance, due to the equilibrium constants. If a parameter distribution is narrow, the resulting distribution of the variables can be computed by expanding them around a set of mean parameter values. We compute the distributions of concentrations, fluxes and probabilities for qualitative variables such as flux directions. The probabilistic framework allows the study of metabolic correlations, and it provides simple measures of variability and stochastic sensitivity. It also shows clearly how the variability of biological systems is related to the metabolic response coefficients.

Animals↗
PubMed2005

Adequacy of a vancomycin dosing regimen in patients receiving high-flux hemodialysis.

BACKGROUND: Some investigators have recommended the convenient practice of administering vancomycin doses during the last hour of the hemodialysis treatment. Accepting that a greater amount of vancomycin is lost to dialysis with this recent approach, the objective of this study is to determine the pharmacokinetics of vancomycin and assess the adequacy of this dosing regimen in maintaining therapeutic predialysis concentrations. METHODS: A sampling of 22 consecutive patients administered intradialytic vancomycin, 1 g, intravenously (IV) and maintenance doses of 500 mg during the last hour of high-flux dialysis sessions was studied. A population-modeling program and Bayesian pharmacokinetic analysis were used to identify all global and unique pharmacokinetic parameters of interest based on measured vancomycin predialysis concentrations. RESULTS: For the 22 patients studied, this regimen achieved the targeted predialysis concentration range of 5 to 20 microg/mL for 96% of levels, whereas more narrowly within 5 to 15 microg/mL for 86% of levels. Average amount of vancomycin removed during a standardized 3- to 4-hour dialytic session ranged from 30% +/- 7% to 38% +/- 8%. Average elimination half-life of vancomycin on hemodialysis treatment was 5.4 hours (interquartile range, 5.0 to 5.9 hours). Patients showed an average predialysis plasma concentration of 11 +/- 3 microg/mL for the first 7 days of therapy. CONCLUSION: Our results indicate that intradialytic dosing with vancomycin using a 1-g IV load and 500 mg IV with subsequent high-flux dialysis sessions conveniently maintains adequate predialysis plasma concentrations. The lack of drug accumulation with this regimen provides convincing support for a limited blood sampling approach to plasma concentration determinations.

Adult↗
PubMed2005

Evidence-based medicine in pathology: an introduction.

Evidence-based medicine (EBM) is a school of thought that has spread rapidly through medicine in the past 2 decades and is eliciting an increasing interest in Anatomic Pathology and Laboratory Medicine. It has been defined as "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients." The environmental factors that created a need for EBM and basic concepts of this discipline are reviewed. Methods for the accrual and critical appraisal of the validity of available evidence and its impact, applicability and usefulness in pathology practice are discussed. Basic concepts of bayesian data analysis with an emphasis on concepts such as prior and posterior probability and the use of "holdout" or "test" data are introduced. The future of EBM in pathology is discussed and potential applications of these concepts to pathology practice and research are proposed.

Clinical Laboratory Techniques↗
PubMed2002

[Hemochromatosis or hemosiderosis? Initial misinterpretation of clinical symptoms and laboratory findings in a 62-year-old patient].

The exact differential diagnosis of iron overload syndromes is mandatory as important therapeutic consequences may derive from a correct diagnosis, especially when hemochromatosis is present. To facilitate diagnostic and therapeutic decisions algorithms and probabilistic calculations based on different frequencies of clinical symptoms and typical laboratory findings of the diseases in question have been proposed. Overestimation and/or underestimation of clinical symptoms and/or laboratory findings in using such calculations, however, may lead to incorrect diagnosis and therapy as demonstrated in this case. We report on a 62-year-old patient with arthralgia, pathologic glucose metabolism, brown skin pigmentation and excessively elevated ferritin and transferrin saturation levels, which initially were interpreted as signs of the assumed underlying disease (hemo-chromatosis) based on a high initial suspicion level and further corroborated by Bayesian probability analysis yielding a probability 99.0 % for the presence of hemochromatosis. Because of this high probability and the patient's wish for treatment phlebotomy was started, but stopped after having obtained negative results of genetic testing and normal quantitative liver iron values. The diagnosis of hemochromatosis had to be revised and symptoms and laboratory findings of this patient were found to be compatible with chronic fatty liver and pathologically altered iron metabolism due to chronic alcohol intake which the patient has initially concealed. The joint pain was explained in terms of chronic degenerative bone destruction, the impaired glucose tolerance seen as the consequence of obesity and the skin pigmentation was ascribed to sun exposure due to the patient's outdoor activities as a hobby farmer not evaluated during initial presentation. The implications and importance of unbiased history taking, critical interpretation of clinical symptoms and laboratory findings in using probabilistic calculations and diagnostic decision analysis are emphasized and the different mechanisms of iron metabolism in hemochromatosis and hemosiderosis are discussed.

Biopsy, Needle↗
PubMed2005

How effective for fold recognition is a potential of mean force that includes relative orientations between contacting residues in proteins?

We estimate the statistical distribution of relative orientations between contacting residues from a database of protein structures and evaluate the potential of mean force for relative orientations between contacting residues. Polar angles and Euler angles are used to specify two degrees of directional freedom and three degrees of rotational freedom for the orientation of one residue relative to another in contacting residues, respectively. A local coordinate system affixed to each residue based only on main chain atoms is defined for fold recognition. The number of contacting residue pairs in the database will severely limit the resolution of the statistical distribution of relative orientations, if it is estimated by dividing space into cells and counting samples observed in each cell. To overcome such problems and to evaluate the fully anisotropic distributions of relative orientations as a function of polar and Euler angles, we choose a method in which the observed distribution is represented as a sum of delta functions each of which represents the observed orientation of a contacting residue, and is evaluated as a series expansion of spherical harmonics functions. The sample size limits the frequencies of modes whose expansion coefficients can be reliably estimated. High frequency modes are statistically less reliable than low frequency modes. Each expansion coefficient is separately corrected for the sample size according to suggestions from a Bayesian statistical analysis. As a result, many expansion terms can be utilized to evaluate orientational distributions. Also, unlike other orientational potentials, the uniform distribution is used for a reference distribution in evaluating a potential of mean force for each type of contacting residue pair from its orientational distribution, so that residue-residue orientations can be fully evaluated. It is shown by using decoy sets that the discrimination power of the orientational potential in fold recognition increases by taking account of the Euler angle dependencies and becomes comparable to that of a simple contact potential, and that the total energy potential taken as a simple sum of contact, orientation, and (phi,psi) potentials performs well to identify the native folds.

Journal Article↗
PubMed2003

A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: application to Mycobacterium tuberculosis.

We describe a postgenomic in silico approach for identifying genes that are likely to be essential and estimate their proportion in haploid genomes. With the knowledge of all sites eligible for mutagenesis and an experimentally determined partial list of nonessential genes from genome mutagenesis, a Bayesian statistical method provides reasonable predictions of essential genes with a subsaturation level of random mutagenesis. For mutagenesis, a transposon such as Himar1 is suitable as it inserts randomly into TA sites. All of the possible insertion sites may be determined a priori from the genome sequence and with this information, data on experimentally hit TA sites may be used to predict the proportion of genes that cannot be mutated. As a model, we used the Mycobacterium tuberculosis genome. Using the Himar1 transposon, we created a genetically defined collection of 1,425 insertion mutants. Based on our Bayesian statistical analysis using Markov chain Monte Carlo and the observed frequencies of transposon insertions in all of the genes, we estimated that the M. tuberculosis genome contains 35% (95% confidence interval, 28%-41%) essential genes. This analysis further revealed seven functional groups with high probabilities of being enriched in essential genes. The PE-PGRS (Pro-Glu polymorphic GC-rich repetitive sequence) family of genes, which are unique to mycobacteria, the polyketide/nonribosomal peptide synthase family, and mycolic and fatty acid biosynthesis gene families were disproportionately enriched in essential genes. At subsaturation levels of mutagenesis with a random transposon such as Himar1, this approach permits a statistical prediction of both the proportion and identities of essential genes of sequenced genomes.

Anti-Bacterial Agents↗
PubMed2006

Phyloclimatic modeling: combining phylogenetics and bioclimatic modeling.

We investigate the impact of past climates on plant diversification by tracking the "footprint" of climate change on a phylogenetic tree. Diversity within the cosmopolitan carnivorous plant genus Drosera (Droseraceae) is focused within Mediterranean climate regions. We explore whether this diversity is temporally linked to Mediterranean-type climatic shifts of the mid-Miocene and whether climate preferences are conservative over phylogenetic timescales. Phyloclimatic modeling combines environmental niche (bioclimatic) modeling with phylogenetics in order to study evolutionary patterns in relation to climate change. We present the largest and most complete such example to date using Drosera. The bioclimatic models of extant species demonstrate clear phylogenetic patterns; this is particularly evident for the tuberous sundews from southwestern Australia (subgenus Ergaleium). We employ a method for establishing confidence intervals of node ages on a phylogeny using replicates from a Bayesian phylogenetic analysis. This chronogram shows that many clades, including subgenus Ergaleium and section Bryastrum, diversified during the establishment of the Mediterranean-type climate. Ancestral reconstructions of bioclimatic models demonstrate a pattern of preference for this climate type within these groups. Ancestral bioclimatic models are projected into palaeo-climate reconstructions for the time periods indicated by the chronogram. We present two such examples that each generate plausible estimates of ancestral lineage distribution, which are similar to their current distributions. This is the first study to attempt bioclimatic projections on evolutionary time scales. The sundews appear to have diversified in response to local climate development. Some groups are specialized for Mediterranean climates, others show wide-ranging generalism. This demonstrates that Phyloclimatic modeling could be repeated for other plant groups and is fundamental to the understanding of evolutionary responses to climate change.

Acclimatization↗
PubMed2003

MrBayes 3: Bayesian phylogenetic inference under mixed models.

MrBayes 3 performs Bayesian phylogenetic analysis combining information from different data partitions or subsets evolving under different stochastic evolutionary models. This allows the user to analyze heterogeneous data sets consisting of different data types-e.g. morphological, nucleotide, and protein-and to explore a wide variety of structured models mixing partition-unique and shared parameters. The program employs MPI to parallelize Metropolis coupling on Macintosh or UNIX clusters.

Algorithms↗
PubMed2003

Mapping determinants of variation in energy metabolism, respiration and flight in Drosophila.

We employed quantitative trait locus (QTL) mapping to dissect the genetic architecture of a hierarchy of functionally related physiological traits, including metabolic enzyme activity, metabolite storage, metabolic rate, and free-flight performance in recombinant inbred lines of Drosophila melanogaster. We identified QTL underlying variation in glycogen synthase, hexokinase, phosphoglucomutase, and trehalase activity. In each case variation mapped away from the enzyme-encoding loci, indicating that trans-acting regions of the genome are important sources of variation within the metabolic network. Individual QTL associated with variation in metabolic rate and flight performance explained between 9 and 35% of the phenotypic variance. Bayesian QTL analysis identified epistatic effects underlying variation in flight velocity, metabolic rate, glycogen content, and several metabolic enzyme activities. A region on the third chromosome was associated with expression of the glucose-6-phosphate branchpoint enzymes and with metabolic rate and flight performance. These genomic regions are of special interest as they may coordinately regulate components of energy metabolism with effects on whole-organism physiological performance. The complex biochemical network is encoded by an equally complex network of interacting genetic elements with potentially pleiotropic effects. This has important consequences for the evolution of performance traits that depend upon these metabolic networks.

Animals↗
PubMed2002

Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period.

Four female and four male crew members, including two of the present authors (R. Walford and T. MacCallum)--seven of the crew being ages 27 to 42 years, and one aged 67 years--were sealed inside Biosphere 2 for two years. During seven eighths of that period they consumed a low-calorie (1750-2100 kcal/d) nutrient-dense diet of vegetables, fruits, nuts, grains, and legumes, with small amounts of dairy, eggs, and meat (approximately 12% calories from protein, approximately 11% from fat, and approximately 77% from complex carbohydrates). They experienced a marked and sustained weight loss of 17 +/- 5%, mostly in the first 8 months. Blood was drawn before entry into Biosphere 2, at many time-points inside it, and four times during the 30 months following exit from it and return to an ad libitum diet. Longitudinal studies of 50 variables on each crew member compared outside and inside values by means of a Bayesian statistical analysis. The data show that physiologic (e.g., body mass index, with a decrease of 19% for men and 13% for women; blood pressure, with a systolic decrease of 25% and a diastolic decrease of 22%), hematologic (e.g., white blood cell count, decreased 31%), hormonal (e.g., insulin, decreased 42%; T3, decreased 19%), biochemical (e.g., blood sugar, decreased 21%; cholesterol, decreased 30%), and a number of additional changes, including values for rT3, cortisol, glycated hemoglobin, plus others, resembled those of rodents or monkeys maintained on a calorie-restricted regime. Significant variations in several substances not hitherto studied in calorie-restricted animals are also reported (e.g., androstenedione, thyroid binding globulin, renin, and transferrin). We conclude that healthy nonobese humans on a low-calorie, nutrient-dense diet show physiologic, hematologic, hormonal, and biochemical changes resembling those of rodents and monkeys on such diets. With regard to the health of humans on such a diet, we observed that despite the selective restriction in calories and marked weight loss, all crew members remained in excellent health and sustained a high level of physical and mental activity throughout the entire 2 years.

Adaptation, Physiological↗
PubMed1994

Drugs-of-abuse testing in urine: statistical approach and experimental comparison of immunochemical and chromatographic techniques.

This study deals with the experimental and statistical comparison of six immunochemical techniques, including noninstrumental on-site and instrumental formats (EIA-EMIT and EZ-SCREEN; FPIA-ADx; RIA-Coat-A-Count; LI-Abuscreen ONTRAK; CBI-Triage), and three chromatographic techniques (TLC-Toxi-Lab; HPLC; HPLC-REMEDi drug profiling system), using GC-MS as a reference technique for analyzing amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates in the urine of various kinds of drug users. The study reports (a) the values of sensitivity, specificity, false-positive rates, and false-negative rates of each technique; (b) the results of bayesian statistical analysis, which are based on prevalence values of the samples examined and expressed as positive and negative predictive values and cumulative predictive values for each single technique and for combinations of paired immunochemical and chromatographic techniques; and (c) the results of a rough classification of the various degrees of predictability of these techniques. Lastly, this study proposes a decision-making process for establishing the best combination of analytical techniques for the goals in question, according to the characteristics and facilities of each laboratory.

Chromatography↗
PubMed1989

Clinical utility of a Bayesian dosing program for phenytoin.

We performed two studies to assess the clinical utility of a Bayesian regression analysis computer program for phenytoin (PHT). In a randomized prospective study of 40 epileptic patients, the dosing program was significantly more accurate (p = 0.002) and less biased (p = 0.02) than a group of physicians at hitting a target PHT serum-concentration. Initial serum PHT concentrations that were not steady state were associated with the largest dosing errors by physicians but did not affect the accuracy of the dosing program. In a second study, we used the dosing program to predict 91 serum concentrations in 31 patients with PHT toxicity after the drug was stopped (initial concentration 26-69 micrograms/ml). The program predicted serum concentrations with a mean error of 3.49 +/- 0.29 micrograms/ml without significant tendency to over- or underpredict. We conclude that this dosing program may aid clinicians by improving dosing accuracy and predicting serum concentrations in patients with PHT toxicity.

Adolescent↗
PubMed2006

Identification of prognostic signatures in breast cancer microarray data using Bayesian techniques.

We apply a new Bayesian data analysis technique (latent process decomposition) to four recent microarray datasets for breast cancer. Compared to hierarchical cluster analysis, for example, this technique has advantages such as objective assessment of the optimal number of sample or gene clusters in the data, penalization of overcomplex models fitting to noise in the data and a common latent space of explanatory variables for samples and genes. Our analysis provides a clearer insight into these datasets, enabling assignment of patients to one of four principal processes, each with a distinct clinical outcome. One process is indolent and associated with under-expression across a number of genes associated with tumour growth. One process is associated with over expression of GRB7 and ERBB2. The most aggressive process is associated with abnormal expression of transcription factor genes, including members of the FOX family of transcription factor genes.

Bayes Theorem↗
PubMed2003

Bounds on isocurvature perturbations from cosmic microwave background and large scale structure data.

We obtain very stringent bounds on the possible cold dark matter, baryon, and neutrino isocurvature contributions to the primordial fluctuations in the Universe, using recent cosmic microwave background and large scale structure data. Neglecting the possible effects of spatial curvature, tensor perturbations, and reionization, we perform a Bayesian likelihood analysis with nine free parameters, and find that the amplitude of the isocurvature component cannot be larger than about 31% for the cold dark matter mode, 91% for the baryon mode, 76% for the neutrino density mode, and 60% for the neutrino velocity mode, at 2sigma, for uncorrelated models. For correlated adiabatic and isocurvature components, the fraction could be slightly larger. However, the cross-correlation coefficient is strongly constrained, and maximally correlated/anticorrelated models are disfavored. This puts strong bounds on the curvaton model.

Journal Article↗
PubMed2006

Molecular systematics of the Philippine malaria vector Anopheles flavirostris.

Allozyme and molecular sequence data from the malaria vector Anopheles flavirostris (Ludlow) (Diptera: Culicidae) were analysed from 34 sites throughout the Philippines, including the type locality, to test the hypothesis that this taxon is a single panmictic species. A finer-scaled allozyme study, of mainly Luzon samples, revealed no fixed genetic differences in sympatric sites and only low levels of variation. We obtained data from partial sequences for the internal transcribed spacer 2 (ITS2) (483 bp), the third domain (D3) (330 bp) of the 28S ribosomal DNA subunit and cytochrome c oxidase subunit I (COI) of mitochondrial DNA (261 bp). No sequence variation was observed for ITS2, only a one base pair difference was observed between Philippine and Indonesian D3 sequences and An. flavirostris sequences were unique, confirming their diagnostic value for this taxon. Sixteen COI haplotypes were identified, giving 25 parsimony informative sites. Neighbour-Joining, Maximum Parsimony, Maximum Likelihood and Bayesian phylogenetic analysis of COI sequences for An. flavirostris and outgroup taxa revealed strong branch support for the monophyly of An. flavirostris, thus confirming that Philippine populations of this taxon comprise a single separate species within the Minimus Subgroup of the Funestus Group. Variation in the behaviour of An. flavirostris is likely to be intraspecific rather than interspecific in origin.

Animals↗
PubMed2004

Stocking impact and migration pattern in an anadromous brown trout (Salmo trutta) complex: where have all the stocked spawning sea trout gone?

We examined polymorphism at seven microsatellite loci among sea trout (Salmo trutta) (n = 846) collected from three areas in the Limfjord (Denmark). We then assessed their potential population source by comparing, using a mixed stock analysis (MSA) Bayesian framework, their genetic composition to that of brown trout collected from 32 tributaries pooled into nine geographical regions (n = 3801) and two hatcheries (n = 222) used for stocking. For each of the three regional sea trout groups (western, central and eastern Limfjord, n = 91, n = 426, n = 329, respectively), MSA was conducted with (i) all individuals in the group, (ii) with the subset of spawning sea trout only and (iii) with the subset of foraging, nonspawning individuals only, a subset that consisted primarily of sea trout caught during their first year at sea. For all three regional sea trout groups, a higher proportion of individuals (regardless of whether they were foraging or spawning) appear to have originated from the rivers that drain locally, than from the rivers that drain in other parts of the Limfjord. This suggests (1) that sea trout, at least during their first year at sea, undertake limited migrations within the Limfjord system and (2) that sea trout on their spawning run were caught close to their natal rivers. The proportion of sea trout of hatchery origin varied widely among all three Limfjord areas and broadly reflected regional stocking histories, with high proportions of sea trout of domestic origin in the east (39.3%), where stocking with domestic trout was practised intensely at the time of sampling, and in the west (57.2%), where a programme of coastal stocking of post smolts took place over several years in the early 1990s. In contrast, in the central Limfjord, where stocking with domestic trout was largely abandoned in the early 1990s, the proportion of sea trout of domestic origin was only 8.5%. Interestingly, for all three regional sea trout groups, virtually no sea trout of hatchery origin were found among the spawning individuals, which were on average larger than the nonspawning sea trout. These results suggest that stocked domestic brown trout that become anadromous experience high mortality at sea and are therefore largely absent among the larger, spawning individuals. We conclude that sea trout of domestic origin exhibit much reduced ability to reproduce and are unlikely to contribute significantly to the local gene pool largely because of a relatively high mortality at sea before the onset of maturity.

Animal Migration↗
PubMed2004

Population structure of loggerhead shrikes in the California Channel Islands.

The loggerhead shrike (Lanius ludovicianus), a songbird that hunts like a small raptor, maintains breeding populations on seven of the eight California Channel Islands. One of the two subspecies, L. l. anthonyi, was described as having breeding populations on six of the islands while a second subspecies, L. l. mearnsi, was described as being endemic to San Clemente Island. Previous genetic studies have demonstrated that the San Clemente Island loggerhead shrike is well differentiated genetically from both L. l. anthonyi and mainland populations, despite the fact that birds from outside the population are regular visitors to the island. Those studies, however, did not include a comparison between San Clemente Island shrikes and the breeding population on Santa Catalina Island, the closest island to San Clemente. Here we use mitochondrial control region sequences and nuclear microsatellites to investigate the population structure of loggerhead shrikes in the Channel Islands. We confirm the genetic distinctiveness of the San Clemente Island loggerhead shrike and, using Bayesian clustering analysis, demonstrate the presence and infer the source of the nonbreeding visitors. Our results indicate that Channel Island loggerhead shrikes comprise three distinct genetic clusters that inhabit: (i) San Clemente Island, (ii) Santa Catalina Island and (iii) the Northern Channel Islands and nearby mainland; they do not support a recent suggestion that all Channel Island loggerhead shrikes should be managed as a single entity.

Animals↗