Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Bayesian dating”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed2004

Estimating absolute rates of synonymous and nonsynonymous nucleotide substitution in order to characterize natural selection and date species divergences.

The rate of molecular evolution can vary among lineages. Sources of this variation have differential effects on synonymous and nonsynonymous substitution rates. Changes in effective population size or patterns of natural selection will mainly alter nonsynonymous substitution rates. Changes in generation length or mutation rates are likely to have an impact on both synonymous and nonsynonymous substitution rates. By comparing changes in synonymous and nonsynonymous rates, the relative contributions of the driving forces of evolution can be better characterized. Here, we introduce a procedure for estimating the chronological rates of synonymous and nonsynonymous substitutions on the branches of an evolutionary tree. Because the widely used ratio of nonsynonymous and synonymous rates is not designed to detect simultaneous increases or simultaneous decreases in synonymous and nonsynonymous rates, the estimation of these rates rather than their ratio can improve characterization of the evolutionary process. With our Bayesian approach, we analyze cytochrome oxidase subunit I evolution in primates and infer that nonsynonymous rates have a greater tendency to change over time than do synonymous rates. Our analysis of these data also suggests that rates have been positively correlated.

Animals↗
PubMed2006

Genetic variation, population structure, and phylogenetic relationships of Triatoma rubida and T. recurva (Hemiptera: Reduviidae: Triatominae) from the Sonoran Desert, insect vectors of the Chagas' disease parasite Trypanosoma cruzi.

Nucleotide and amino acid sequence data from the mitochondrial cytochrome b (Cytb) and cytochrome c oxidase subunit I (COI) gene segments were used to gain insights into the population biology and phylogenetic relationships of two species of hematophagous kissing bugs (Hemiptera: Reduviidae: Triatominae) from the Sonoran Desert of northwestern Mexico and southern Arizona, USA, Triatoma rubida (Uhler, 1894) and T. recurva (Stål, 1868), both of which are vectors of the protozoan parasite Trypanosoma cruzi responsible for Chagas' disease. Analysis of molecular variance of gene sequences indicated significant structure among populations of both species from widely separated geographic localities. Phylogenetic analyses of gene and amino acid sequences employing both Bayesian and parsimony methods showed that T. recurva clustered within the phyllosoma complex of Triatoma species from central and southern Mexico with high statistical support, and that it was closely related to T. longipennis. Triatoma dimidiata also was shown to be closely related to the phyllosoma complex, as was T. sanguisuga which has historically been assigned to the lecticularia complex. Analyses of gene sequences were unable to confidently resolve relationships of T. rubida, although weak support for a T. nitida+T. rubida clade was seen under certain conditions. A provisional calibration of a mitochondrial DNA molecular clock for T. rubida, based on geological dates for the vicariant separation of the Baja California peninsula from mainland Mexico, suggested that pairwise sequence divergences for the Cytb and COI genes were 1.1-1.8% and 0.6-1.0% per million years, respectively. Two highly supported sympatric lineages of T. rubida uhleri from southern Arizona, which are hypothesized to have diverged approximately 550,000-900,000 years ago, were detected in the Cytb gene trees.

Amino Acid Sequence↗
PubMed2003

Genetic identification of two sibling species of Lutzomyia longipalpis (Diptera: Psychodidae) that produce distinct male sex pheromones in Sobral, Ceará State, Brazil.

Lutzomyia longipalpis, the main sandfly vector for New World visceral leishmaniasis is a complex of an as yet undefined number of sibling species. At present, there is no consensus on the status (single species vs. species complex) of Brazilian populations. We applied five microsatellite loci to test the hypothesis that L. longipalpis occurs as two sympatric cryptic species in Sobral, Ceará State, Brazil as predicted by male sex pheromone chemotypes described previously for field specimens from this site [S-9-methyl-germacrene-B (9MGB) and a cembrene compound]. Abdominal spot morphology corresponds with pheromone type at this locality (9MGB in '1 spot' males and cembrene in '2 spot' males). Genotype data from 190 wild-caught L. longipalpis specimens collected in October 1999 and April 2001 were used to estimate genetic differentiation between the two sex pheromone populations and sampling dates. No significant (P > 0.05) genetic differences were found between the 1999 and 2001 9MGB samples (theta = 0.018; RST = -0.005), and genetic differentiation was low between the cembrene collections (theta = 0.037, P < 0.05; RST = -0.043, P > 0.05). By contrast, highly divergent allelic frequencies (largely at two microsatellite loci) corresponded to significant (P > 0.05) genetic differentiation (theta = 0.221; RST = 0.215) for all comparisons between samples with different pheromones. When pheromone samples were pooled across sample date, genetic differentiation was high (theta = 0.229; P < 0.001; Nem = 0.84). The allele frequency distribution at each of the five microsatellite loci was similar for males and females from the two collection years. Two of these loci showed highly divergent allele frequencies in the two sex pheromone populations. This was reflected in the highly significant genetic differentiation obtained from the male genotypes, between populations producing different pheromones (theta = 0.229-0.268; P < 0.0001 for the 2001 and theta = 0.254-0.558; P < 0.0001 for the 1999 collections, respectively). Similar results were obtained when the females, assigned to a pheromone type, were included in the analysis. Both a Bayesian analysis of the data set and a population assignment test provided strong evidence for two distinct populations corresponding to pheromone type. Given its genotype, the probability of assigning a 9MGB male to the original 9MGB population was 100% once the two years' collections were pooled. For cembrene-producing '2 spot' males this probability although still high, was lower than for 9MGB males, at 86%. This microsatellite data together with previously reported reproductive isolation between the two Sobral populations confirm that premating barriers are important in speciation of L. longipalpis.

Animals↗
PubMedDate not supplied

Medical decision making with incomplete evidence--choosing a platelet glycoprotein IIbIIIa receptor inhibitor for percutaneous coronary interventions.

BACKGROUND: Medical decision making must often be performed despite incomplete evidence. An example is the choice of a glycoprotein IIb/IIIa (GP2b3a) inhibitor, a class of potent antiplatelet medications, as adjunctive therapy during percutaneous coronary interventions (PCIs). GP2b3a inhibitor efficacy in reducing adverse outcomes has been well documented with multiple placebo-controlled randomized trials, but there is a paucity of comparative data about their individual equivalency. Substantial cost differentials are also present between the drugs. METHODS: A systematic review of the literature was performed to identify all randomized placebo-controlled trials of GP2b3a inhibitors as adjunctive therapy for PCI. Three complimentary methods were used to assist in decision making regarding drug equivalency. First, the data from the single direct comparative trial are analyzed from a Bayesian perspective. Next, prior information from other GP2b3a inhibitor trials in similar but not identical patient populations is incorporated. In the 3rd method, indirect comparisons of GP2b3a inhibitors are carried out using a hierarchical meta-analytic model of the placebo-controlled trials identified by the systematic review. RESULTS: A total of 12 randomized trials were identified involving 3 agents (abciximab, eptifibatide, tirofiban), but only 1 involved a direct comparison of 2 drugs (abciximab v. tirofiban). In contradiction to the original publication, the authors' Bayesian analysis both without (method 1) and with (method 2) the inclusion of some prior information suggests a reasonable probability of equivalency. The indirect comparisons from all randomized placebo-controlled trials (method 3) also failed to provide support for superiority of any agent over the others. CONCLUSION: Decision making with incomplete evidence is a difficult but frequently occurring medical dilemma. The authors propose 3 methods that may elucidate the process and illustrate them in the context of the choice of GP2b3a inhibitor for adjunctive therapy during PCI. Further data may or may not eventually lead to a different conclusion, but based on the evidence available to date, the authors' 3 methods suggest clinical equivalency between GP2b3a inhibitors, in contrast to the initial conclusions from the single comparative randomized trial.

Angioplasty, Balloon, Coronary↗
PubMed1986

Progress toward a more ethical method for clinical trials.

Methodology for conducting clinical trials of new drugs and treatments on people need not be regarded as fixed. After reviewing the currently most popular method (randomization) and its ethical problems, this paper explores the possibilities of a new method for conducting such trials. It relies on new Bayesian technology for eliciting the opinions of medical experts. These opinions are conditioned on specific predictor variables, and are held in a computer. At any stage in a trial, these opinions can be updated in the computer using the information collected in the trial up to that point. Consider as an admissible treatment for a patient having specific values of predictor variables only those treatments that at least one expert regards as best (in the computer model) for this patient. It is proposed that only admissible treatments, so defined, be allowed to be assigned to the patient. The ethical and statistical consequences of this principle are explored. Experience to date with a trial at Johns Hopkins designed on this principle is reported.

Bayes Theorem↗
PubMed2006

Adherence to antiretroviral therapy in sub-Saharan Africa and North America: a meta-analysis.

CONTEXT: Adherence to antiretroviral therapy is a powerful predictor of survival for individuals living with human immunodeficiency virus (HIV) and AIDS. Concerns about incomplete adherence among patients living in poverty have been an important consideration in expanding the access to antiretroviral therapy in sub-Saharan Africa. OBJECTIVE: To evaluate estimates of antiretroviral therapy adherence in sub-Saharan Africa and North America. DATA SOURCES: Eleven electronic databases were searched along with major conference abstract databases (inclusion dates: inception of database up until April 18, 2006) for all English-language articles and abstracts; and researchers and treatment advocacy groups were contacted. Study Selection and Data Abstraction To best reflect the general population, studies of mixed populations in both North America and Africa were selected. Studies evaluating specific populations such as men only, homeless individuals, or drug users, were excluded. The data were abstracted in duplicate on study adherence outcomes, thresholds used to determine adherence, and characteristics of the populations. A random-effects meta-analysis was performed in which heterogeneity was examined using multivariable random-effects logistic regression. A sensitivity analysis was performed using Bayesian methods. DATA SYNTHESIS: Thirty-one studies from North America (28 full-text articles and 3 abstracts) and 27 studies (9 full-text articles and 18 abstracts) from sub-Saharan Africa were included. African studies represented 12 sub-Saharan countries. Of the North American studies, 71% used patient self-report to assess adherence; this was true of 66% of the African assessments. Studies reported similar thresholds for adherence monitoring (eg, 100%, >95%, >90%, >80%). A pooled analysis of the North American studies (17,573 patients total) indicated a pooled estimate of 55% (95% confidence interval, 49%-62%; I2, 98.6%) of the populations achieving adequate levels of adherence. Our pooled analysis of African studies (12,116 patients total) indicated a pooled estimate of 77% (95% confidence interval, 68%-85%; I2, 98.4%). Study continent, adherence thresholds, and study quality were significant predictors of heterogeneity. Bayesian analysis was used as an alternative statistical method for combining adherence rates and provided similar findings. CONCLUSION: Our findings indicate that favorable levels of adherence, much of which was assessed via patient self-report, can be achieved in sub-Saharan African settings and that adherence remains a concern in North America.

Africa South of the Sahara↗
PubMed2005

Probabilistic annotation of protein sequences based on functional classifications.

BACKGROUND: One of the most evident achievements of bioinformatics is the development of methods that transfer biological knowledge from characterised proteins to uncharacterised sequences. This mode of protein function assignment is mostly based on the detection of sequence similarity and the premise that functional properties are conserved during evolution. Most automatic approaches developed to date rely on the identification of clusters of homologous proteins and the mapping of new proteins onto these clusters, which are expected to share functional characteristics. RESULTS: Here, we inverse the logic of this process, by considering the mapping of sequences directly to a functional classification instead of mapping functions to a sequence clustering. In this mode, the starting point is a database of labelled proteins according to a functional classification scheme, and the subsequent use of sequence similarity allows defining the membership of new proteins to these functional classes. In this framework, we define the Correspondence Indicators as measures of relationship between sequence and function and further formulate two Bayesian approaches to estimate the probability for a sequence of unknown function to belong to a functional class. This approach allows the parametrisation of different sequence search strategies and provides a direct measure of annotation error rates. We validate this approach with a database of enzymes labelled by their corresponding four-digit EC numbers and analyse specific cases. CONCLUSION: The performance of this method is significantly higher than the simple strategy consisting in transferring the annotation from the highest scoring BLAST match and is expected to find applications in automated functional annotation pipelines.

Algorithms↗
PubMed2006

Tree and rate estimation by local evaluation of heterochronous nucleotide data.

MOTIVATION: Heterochronous gene sequence data is important for characterizing the evolutionary processes of fast-evolving organisms such as RNA viruses. A limited set of algorithms exists for estimating the rate of nucleotide substitution and inferring phylogenetic trees from such data. The authors here present a new method, Tree and Rate Estimation by Local Evaluation (TREBLE) that robustly calculates the rate of nucleotide substitution and phylogeny with several orders of magnitude improvement in computational time. METHODS: For the basis of its rate estimation TREBLE novelly utilizes a geometric interpretation of the molecular clock assumption to deduce a local estimate of the rate of nucleotide substitution for triplets of dated sequences. Averaging the triplet estimates via a variance weighting yields a global estimate of the rate. From this value, an iterative refinement procedure relying on statistical properties of the triplets then generates a final estimate of the global rate of nucleotide substitution. The estimated global rate is then utilized to find the tree from the pairwise distance matrix via an UPGMA-like algorithm. RESULTS: Simulation studies show that TREBLE estimates the rate of nucleotide substitution with point estimates comparable with the best of available methods. Confidence intervals are comparable with that of BEAST. TREBLE's phylogenetic reconstruction is significantly improved over the other distance matrix method but not as accurate as the Bayesian algorithm. Compared with three other algorithms, TREBLE reduces computational time by a minimum factor of 3000. Relative to the algorithm with the most accurate estimates for the rate of nucleotide substitution (i.e. BEAST), TREBLE is over 10,000 times more computationally efficient. AVAILABILITY: jdobrien.bol.ucla.edu/TREBLE.html

Chromosome Mapping↗
PubMed2025

Distinct patterns of de novo coding variants contribute to Tourette Syndrome etiology.

Tourette syndrome (TS) is a highly heritable childhood-onset neuropsychiatric disorder characterized by persistent motor and vocal tics. While both common and rare variants contribute to TS susceptibility, the role of rare de novo mutations (DNMs) remains incompletely characterized. Here, we report findings from the largest TS whole-exome sequencing study to date, analyzing 1,466 TS trios alongside 6,714 autism spectrum disorder (ASD) trios and 5,880 unaffected sibling controls from the Simons Simplex Collection (SSC) and SPARK cohorts. Leveraging a trio-based design across these cohorts enabled calibrated assessment of DNM burden while controlling for background mutation rates. We observed a significant exome-wide enrichment of protein-truncating DNMs in TS probands, particularly within genes intolerant to loss-of-function variation (pLI &#x2265; 0.9), with little contribution from damaging missense variants. Notably, TS probands did not exhibit enrichment in previously implicated ASD or developmental delay (DD) genes, but elsewhere in the genome, suggesting a distinct rare variant architecture. Using a Bayesian statistical framework that integrates both de novo and rare inherited coding variants, we identified three candidate TS risk genes with FDR &#x2264; 0.05: PPP5C , EXOC1 , and GXYLT1 . Literature shows that they have prior links to neurodevelopmental and psychiatric disorders. These findings reveal a rare variant burden in TS that is genetically distinguishable from ASD, underscore the importance of loss-of-function mutations in TS risk, and nominate novel candidate genes for future functional investigation.

Journal Article↗
PubMed2005

Are the acute effects of particulate matter on mortality in the National Morbidity, Mortality, and Air Pollution Study the result of inadequate control for weather and season? A sensitivity analysis using flexible distributed lag models.

Time-series studies have linked daily variations in nonaccidental deaths with daily variations in ambient particulate matter air pollution, while controlling for qualitatively larger influences of weather and season. Although time-series analyses typically include nonlinear terms for weather and season, questions remain as to whether models to date have completely controlled for these important predictors. In this paper, the authors use two flexible versions of distributed lag models to control extensively for the confounding effects of weather and season. One version builds on the current approach to controlling for weather, while the other version offers a new approach. The authors conduct a comprehensive sensitivity analysis of the particulate matter-mortality relation by applying these methods to the recently updated National Morbidity, Mortality, and Air Pollution Study database that comprises air pollution, weather, and mortality time series from 1987 to 2000 for 100 US cities. They combine city-specific estimates of the short-term effects of particulate matter on mortality using a Bayesian hierarchical model. They conclude that, within the broad classes of models considered, national average estimates of particulate matter relative risk are consistent with previous estimates from this study and are robust to model specification for weather and seasonal confounding.

Aged↗
PubMed2006

Testing the molecular clock: molecular and paleontological estimates of divergence times in the Echinoidea (Echinodermata).

The phylogenetic relationships of 46 echinoids, with representatives from 13 of the 14 ordinal-level clades and about 70% of extant families commonly recognized, have been established from 3 genes (3,226 alignable bases) and 119 morphological characters. Morphological and molecular estimates are similar enough to be considered suboptimal estimates of one another, and the combined data provide a tree that, when calibrated against the fossil record, provides paleontological estimates of divergence times and completeness of their fossil record. The order of branching on the cladogram largely agrees with the stratigraphic order of first occurrences and implies that their fossil record is more than 85% complete at family level and at a resolution of 5-Myr time intervals. Molecular estimates of divergence times derived from applying both molecular clock and relaxed molecular clock models are concordant with estimates based on the fossil record in up to 70% of cases, with most concordant results obtained using Sanderson's semiparametric penalized likelihood method and a logarithmic-penalty function. There are 3 regions of the tree where molecular and fossil estimates of divergence time consistently disagree. Comparison with results obtained when molecular divergence dates are estimated from the combined (morphology + gene) tree suggests that errors in phylogenetic reconstruction explain only one of these. In another region the error most likely lies with the paleontological estimates because taxa in this region are demonstrated to have a very poor fossil record. In the third case, morphological and paleontological evidence is much stronger, and the topology for this part of the molecular tree differs from that derived from the combined data. Here the cause of the mismatch is unclear but could be methodological, arising from marked inequality of molecular rates. Overall, the level of agreement reached between these different data and methodological approaches leads us to believe that careful application of likelihood and Bayesian methods to molecular data provides realistic divergence time estimates in the majority of cases (almost 80% in this specific example), thus providing a remarkably well-calibrated phylogeny of a character-rich clade of ubiquitous marine benthic invertebrates.

Animals↗
PubMed2007

Chromosome painting and molecular dating indicate a low rate of chromosomal evolution in golden moles (Mammalia, Chrysochloridae).

Golden moles (Chrysochloridae) are poorly known subterranean mammals endemic to Southern Africa that are part of the superordinal clade Afrotheria. Using G-banding and chromosome painting we provide a comprehensive comparison of the karyotypes of five species representing five of the nine recognized genera: Amblysomus hottentotus, Chrysochloris asiatica, Chrysospalax trevelyani, Cryptochloris zyli and Eremitalpa granti. The species are karyotypically highly conserved. In total, only four changes were detected among them. Eremitalpa granti has the most derived karyotype with 2n = 26 and differs from the remaining species (all of whom have 2n = 30) by one centric and one telomere:telomere fusion. In addition, two intrachromosomal rearrangements were detected in A. hottentotus. The painting probes also suggest the presence of a unique satellite DNA family located on chromosomes 11 and 12 of both C. asiatica and C. zyli. This represents a synapomorphy linking these two sympatric species as sister taxa. A molecular clock was calibrated adopting a relaxed Bayesian approach for multigene data sets comprising publicly available sequences derived from five gene fragments representative of three golden moles and 39 other eutherian species. The data suggest that golden moles diverged from a common ancestor approximately 28.5 mya (95% credibility interval = 21.5-36.5 mya). Based on an inferred chrysochlorid ancestral karyotype of 2n = 30, the estimated rate of 0.7 rearrangements per 10 my (95% Credibility Interval = 0.54-0.93) differs from the 'default rate' of mammalian chromosomal evolution which has been estimated at one change per 10 million years, thus placing the Chrysochloridae among the slower-evolving chromosomal lineages thus far recorded.

Animals↗
PubMed2001

Data mining in the US Vaccine Adverse Event Reporting System (VAERS): early detection of intussusception and other events after rotavirus vaccination.

The Vaccine Adverse Event Reporting System (VAERS) is the US passive surveillance system monitoring vaccine safety. A major limitation of VAERS is the lack of denominator data (number of doses of administered vaccine), an element necessary for calculating reporting rates. Empirical Bayesian data mining, a data analysis method, utilizes the number of events reported for each vaccine and statistically screens the database for higher than expected vaccine-event combinations signaling a potential vaccine-associated event. This is the first study of data mining in VAERS designed to test the utility of this method to detect retrospectively a known side effect of vaccination-intussusception following rotavirus (RV) vaccine. From October 1998 to December 1999, 112 cases of intussusception were reported. The data mining method was able to detect a signal for RV-intussusception in February 1999 when only four cases were reported. These results demonstrate the utility of data mining to detect significant vaccine-associated events at early date. Data mining appears to be an efficient and effective computer-based program that may enhance early detection of adverse events in passive surveillance systems.

Adverse Drug Reaction Reporting Systems↗
PubMed1989

Enumerative, Bayesian, and analytic statistical analysis of nosocomial infection for quality improvement: first of two parts.

Readmission rates are used by the Health Care Financing Administration (HCFA) as an indicator of a hospital's quality of care. Specifically, HCFA seeks to relate readmission to complications of the primary admission. A recent study at the Cleveland Clinic Foundation examined patients readmitted within 30 days of dismissal during two non-consecutive months to the cardiovascular surgery, cardiology, and gastroenterology services at this 1,008 bed hospital, accounting for 31% (1640-5342) of all hospital discharges. Only 17% (25/149) of readmissions were due to a complication of the previous hospital admission. Examining those who were readmitted for complications of their primary admission, we found that 36% (9/25) of such readmitted patients had infections that occurred during their primary admission. Otherwise stated, 5.4% (9/149) of readmissions were for nosocomial infections. These patients were compared with 20 retrospectively matched, non-readmitted patients chosen randomly from a group of 100 patients retrospectively matched for gender, age, type, and date of surgery. Using these controls, a computer-based expert system was used to help identify patient variables that are associated with readmission due to nosocomial infection. We found if a patient had (1) a weight less than 66 Kilograms or (2) had a first postoperative total serum protein greater than 6.1 or (3) was reoperated, we could predict with 100% specificity and 60% sensitivity that the patient would have an unplanned readmission. Total readmission rates do not accurately reflect complications of the primary admission.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Self-monitoring of glucose in type 2 diabetes mellitus: a Bayesian meta-analysis of direct and indirect comparisons.

OBJECTIVE: To evaluate the relative effectiveness of interventions with self-monitoring blood glucose and self-monitoring of urine glucose, versus interventions without self-monitoring, in terms of HbA(1c) reductions in type 2 diabetes mellitus. METHODS: Thirteen published full reports on randomised controlled trials investigating the effects of self-monitoring glucose were identified by a systematic search of Medline, Embase, the Cochrane Library (1966-Nov 2005) and previous reviews. Three types of studies were included: self-monitoring of blood glucose versus no self-monitoring, self-monitoring of blood glucose versus self-monitoring of urine glucose and self-monitoring of blood glucose with regular feedback versus monitoring without feedback. The internal validity of studies was assessed systematically by two reviewers, using 13 criteria of a validated list. Results from the three types of studies were analysed simultaneously with a Bayesian metaanalysis of direct and indirect comparisons. RESULTS: Adjusted for baseline HbA(1c) level and internal validity, interventions with self-monitoring of blood glucose showed a reduction in HbA(1c) of 0.40 percentage-points (%) (95% credible interval [CrI] 0.07 to 0.70%) in comparison to interventions without self-monitoring. Regular feedback more than doubled the HbA(1c) reduction. Self-monitoring of urine glucose showed comparable results to interventions without self-monitoring (0.02% decrease in HbA(1c); 95% CrI -0.62 to 0.70%). There is a 88% probability that interventions with self-monitoring blood glucose are more effective than interventions with urine glucose monitoring (relative reduction in HbA(1c) is 0.38%, 95% CrI -0.30 to 1.00%). CONCLUSION: The randomized clinical trials performed to date provided positive results on the effectiveness of interventions with self-monitoring of blood glucose in type 2 diabetes mellitus. Regular medical feedback of the monitored HbA(1c) levels is important. Furthermore, self-monitoring of blood glucose is likely to be more effective than self-monitoring of urine glucose.

Bayes Theorem↗
PubMed1999

Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients.

The complete pharmacokinetics (PK) of (R)- and (S)-cyclophosphamide (CP) and their dechloroethylated (DCE) metabolites have not been reported to date. We collected plasma and urine samples from 12 cancer patients and determined concentrations of both enantiomers of CP and DCE-CP using a chiral GC-MS method. All concentrations of (R)-CP, (S)-CP, (R)-DCE-CP, and (S)-DCE-CP were simultaneously modeled using an enantiospecific compartmental PK model. A population PK analysis was performed. Enantiospecific differences between (R)- and (S)-CP were found for the formation clearance of CP to the DCE metabolites (Clf: 0.25 (R) vs. 0.14 (S) L/h). No difference was found between enantiomers for Cl40H, Cld, Cl(m)R, ClT, or T1/2. In contrast to the adolescent and adult group of patients, a child (6 years old) appeared to have a very different PK and metabolic profile (Bayesian control analysis). Proportions of the (R,S)-CP doses transformed to the (R)-DCE- and (S)-DCE-CP were much higher (R: 25 vs. 1.9%, and S: 38 vs. 3.6%), while formation of active metabolites was much lower (R: 42 vs. 74%, and S: 48 vs. 77%). CP appears to be enantioselectively metabolized to the DCE metabolites. This PK model can evaluate the proportion of a CP dose that is transformed to toxic or active metabolites. It may therefore be used to optimize CP treatment, to identify important drug interactions and/or patients with an abnormal metabolic profile.

Adolescent↗
PubMed2007

Phylogenetic origins of the Himalayan endemic Dolomiaea, Diplazoptilon and Xanthopappus (Asteraceae: Cardueae) based on three DNA regions.

BACKGROUND AND AIMS: It is an enduring question as to the mechanisms leading to the high diversity and the processes producing endemics with unusual morphologies in the Himalayan alpine region. In the present study, the phylogenetic relationships and origins of three such endemic genera were analysed, Dolomiaea, Diplazoptilon and Xanthopappus, all in the tribe Cardueae of Asteraceae. METHODS: The nuclear rDNA internal transcribed spacer (ITS) and plastid trnL-F and psbA-trnH regions of these three genera were sequenced. The same regions for other related genera in Cardueae were also sequenced or downloaded from GenBank. Phylogenetic trees were constructed from individual and combined data sets of the three types of sequences using maximum parsimony, maximum likelihood and Bayesian analyses. KEY RESULTS: The phylogenetic tree obtained allowed earlier hypotheses concerning the relationships of these three endemic genera based on gross morphology to be rejected. Frolovia and Saussurea costus were deeply nested within Dolomiaea, and the strong statistical support for the Dolomiaea-Frolovia clade suggested that circumscription of Dolomiaea should be more broadly redefined. Diplazoptilon was resolved as sister to Himalaiella, and these two together are sister to Lipschitziella. The clade comprising these three genera is sister to Jurinea, and together these four genera are sister to the Dolomiaea-Frolovia clade. Xanthopappus, previously hypothesized to be closely related to Carduus, was found to be nested within a well-supported but not fully resolved Onopordum group with Alfredia, Ancathia, Lamyropappus, Olgaea, Synurus and Syreitschikovia, rather than the Carduus group. The crude dating based on ITS sequence divergence revealed that the divergence time of Dolomiaea-Frolovia from its sister group probably occurred 13.6-12.2 million years ago (Ma), and the divergence times of the other two genera, Xanthopappus and Diplazoptilon, from their close relatives around 5.7-4.7 Ma and 2.0-1.6 Ma, respectively. CONCLUSIONS: The findings provide an improved understanding of the intergeneric relationships in Cardueae. The crude calibration of lineages indicates that the uplifts of the Qiinghai-Tibetan Plateau since the Miocene might have served as a continuous stimulus for the production of these morphologically aberrant endemic elements of the Himalayan flora.

Asteraceae↗
PubMed2006

Functional diversification of B MADS-box homeotic regulators of flower development: Adaptive evolution in protein-protein interaction domains after major gene duplication events.

B-class MADS-box genes have been shown to be the key regulators of petal and stamen specification in several eudicot model species such as Arabidopsis thaliana, Antirrhinum majus, and Petunia hybrida. Orthologs of these genes have been found across angiosperms and gymnosperms, and it is thought that the basic regulatory function of B proteins is conserved in seed plant lineages. The evolution of B genes is characterized by numerous duplications that might represent key elements fostering the functional diversification of duplicates with a deep impact on their role in the evolution of the floral developmental program. To evaluate this, we performed a rigorous statistical analysis with B gene sequences. Using maximum likelihood and Bayesian methods, we estimated molecular substitution rates and determined the selective regimes operating at each residue of B proteins. We implemented tests that rely on phylogenetic hypotheses and codon substitution models to detect significant differences in substitution rates (DSRs) and sites under positive adaptive selection (PS) in specific lineages before and after duplication events. With these methods, we identified several protein residues fixed by PS shortly after the origin of PISTILLATA-like and APETALA3-like lineages in angiosperms and shortly after the origin of the euAP3-like lineage in core eudicots, the 2 main B gene duplications. The residues inferred to have been fixed by positive selection lie mostly within the K domain of the protein, which is key to promote heterodimerization. Additionally, we used a likelihood method that accommodates DSRs among lineages to estimate duplication dates for AP3-PI and euAP3-TM6, calibrating with data from the fossil record. The dates obtained are consistent with angiosperm origins and diversification of core eudicots. Our results strongly suggest that novel multimer formation with other MADS proteins could have been crucial for the functional divergence of B MADS-box genes. We thus propose a mechanism of functional diversification and persistence of gene duplicates by the appearance of novel multimerization capabilities after duplications. Multimer formation in different combinations of regulatory proteins can be a mechanistic basis for the origin of novel regulatory functions and a gene regulatory mechanism for the appearance of morphological innovations.

Amino Acid Sequence↗