Biomedical subjects

Marc A Suchard

Publications and source records attributed to Marc A Suchard.

26 records · Page 2Linked to original sources

PubMed2004

Evolution of human immunodeficiency virus type 1 coreceptor usage during antiretroviral Therapy: a Bayesian approach.

There is substantial evidence for ongoing replication and evolution of human immunodeficiency virus type 1 (HIV-1), even in individuals receiving highly active antiretroviral therapy. Viral evolution in the presence of antiviral therapy needs to be considered when developing new therapeutic strategies. Phylogenetic analyses of HIV-1 sequences can be used for this purpose but may give rise to misleading results if rates of intrapatient evolution differ significantly. To improve analyses of HIV-1 evolution relevant to studies of pathogenesis and treatment, we developed a Bayesian hierarchical model that incorporates all available sequence data while simultaneously allowing the phylogenetic parameters of each patient to vary. We used this method to examine evolutionary changes in HIV-1 coreceptor usage in response to treatment. We examined patients whose viral populations exhibited a shift in coreceptor utilization in response to therapy. CXCR4 (X4) strains emerged in each patient but were suppressed following initiation of new antiretroviral regimens, so that CCR5-utilizing (R5) strains predominated. By phylogenetically reconstructing the evolutionary relationship of HIV-1 obtained longitudinally from each patient, it was possible to examine the origin of the reemergent R5 virus. Using our Bayesian hierarchical approach, we found that the reemergent R5 virus detectable after therapy was more closely related to the predecessor R5 virus than to the X4 strains. The Bayesian hierarchical approach, unlike more traditional methods, makes it possible to evaluate competing hypotheses across patients. This model is not limited to analyses of HIV-1 but can be used to elucidate evolutionary processes for other organisms as well.

Antiretroviral Therapy, Highly Active↗

PubMed2003

Interplay of chemotaxis and chemokinesis mechanisms in bacterial dynamics.

Motivated by observations of the dynamics of Myxococcus xanthus, we present a self-interacting random walk model that describes the competition between chemokinesis and chemotaxis. Cells are constrained to move in one dimension, but release a chemical chemoattractant at a steady state. The bacteria sense the chemical that they produce. The probability of direction reversals is modeled as a function of both the absolute level of chemoattractant sensed directly under each cell as well as the gradient sensed across the length of the cell. If the chemical does not degrade or diffuse rapidly, the one-dimensional trajectory depends on the entire past history of the trajectory. We derive the corresponding Fokker-Planck equations, use an iterative mean-field approach that we solve numerically for short times, and perform extensive Monte Carlo simulations of the model. Cell positional distributions and the associated moments are computed in this feedback system. Average drift and mean squared displacements are found. Crossover behaviors among different diffusion regimes are found.

Bacterial Physiological Phenomena↗

PubMed2003

Testing a molecular clock without an outgroup: derivations of induced priors on branch-length restrictions in a Bayesian framework.

We propose a Bayesian method for testing molecular clock hypotheses for use with aligned sequence data from multiple taxa. Our method utilizes a nonreversible nucleotide substitution model to avoid the necessity of specifying either a known tree relating the taxa or an outgroup for rooting the tree. We employ reversible jump Markov chain Monte Carlo to sample from the posterior distribution of the phylogenetic model parameters and conduct hypothesis testing using Bayes factors, the ratio of the posterior to prior odds of competing models. Here, the Bayes factors reflect the relative support of the sequence data for equal rates of evolutionary change between taxa versus unequal rates, averaged over all possible phylogenetic parameters, including the tree and root position. As the molecular clock model is a restriction of the more general unequal rates model, we use the Savage-Dickey ratio to estimate the Bayes factors. The Savage-Dickey ratio provides a convenient approach to calculating Bayes factors in favor of sharp hypotheses. Critical to calculating the Savage-Dickey ratio is a determination of the prior induced on the modeling restrictions. We demonstrate our method on a well-studied mtDNA sequence data set consisting of nine primates. We find strong support against a global molecular clock, but do find support for a local clock among the anthropoids. We provide mathematical derivations of the induced priors on branch length restrictions assuming equally likely trees. These derivations also have more general applicability to the examination of prior assumptions in Bayesian phylogenetics.

Animals↗

PubMed2003

Hierarchical phylogenetic models for analyzing multipartite sequence data.

Debate exists over how to incorporate information from multipartite sequence data in phylogenetic analyses. Strict combined-data approaches argue for concatenation of all partitions and estimation of one evolutionary history, maximizing the explanatory power of the data. Consensus/independence approaches endorse a two-step procedure where partitions are analyzed independently and then a consensus is determined from the multiple results. Mixtures across the model space of a strict combined-data approach and a priori independent parameters are popular methods to integrate these methods. We propose an alternative middle ground by constructing a Bayesian hierarchical phylogenetic model. Our hierarchical framework enables researchers to pool information across data partitions to improve estimate precision in individual partitions while permitting estimation and testing of tendencies in across-partition quantities. Such across-partition quantities include the distribution from which individual topologies relating the sequences within a partition are drawn. We propose standard hierarchical priors on continuous evolutionary parameters across partitions, while the structure on topologies varies depending on the research problem. We illustrate our model with three examples. We first explore the evolutionary history of the guinea pig (Cavia porcellus) using alignments of 13 mitochondrial genes. The hierarchical model returns substantially more precise continuous parameter estimates than an independent parameter approach without losing the salient features of the data. Second, we analyze the frequency of horizontal gene transfer using 50 prokaryotic genes. We assume an unknown species-level topology and allow individual gene topologies to differ from this with a small estimable probability. Simultaneously inferring the species and individual gene topologies returns a transfer frequency of 17%. We also examine HIV sequences longitudinally sampled from HIV+ patients. We ask whether posttreatment development of CCR5 coreceptor virus represents concerted evolution from middisease CXCR4 virus or reemergence of initial infecting CCR5 virus. The hierarchical model pools partitions from multiple unrelated patients by assuming that the topology for each patient is drawn from a multinomial distribution with unknown probabilities. Preliminary results suggest evolution and not reemergence.

Animals↗

PubMed2003

Are you my mother? Bayesian phylogenetic inference of recombination among putative parental strains.

Reconstructing evolutionary relationships using Bayesian inference has become increasingly popular due to the ability of Bayesian inference to handle complex models of evolution. In this review we concentrate on inference of recombination events between strains of viruses when these events are sporadic, ie rare relative to point mutations. Bayesian inference is especially attractive in the detection of recombination events because it allows for simultaneous inferences about the presence, number and location of crossover points and the identification of parental sequences. Current frequentist recombination identification falls into a sequential testing trap. The most likely parental sequences and crossover points are identified using the data and then the certainty of recombination is assessed conditional on this identification. After briefly outlining basic phylogenetic models, Bayesian inference and Markov chain Monte Carlo (MCMC) computation, we summarise three different approaches to recombination detection and discuss current challenges in applying Bayesian phylogenetic inference of recombination.

Algorithms↗

PubMed2002

Oh brother, where art thou? A Bayes factor test for recombination with uncertain heritage.

Current methods to identify recombination between subtypes of human immunodeficiency virus 1 (HIV-1) fall into a sequential testing trap, in which significance is assessed conditional on parental representative sequences and crossover points (COPs) that maximize the same test statistic. We overcame this shortfall by testing for recombination while inferring parental heritage and COPs using an extended Bayesian multiple change-point model. The model assumes that aligned molecular sequence data consist of an unknown number of contiguous segments that may support alternative topologies or varying evolutionary pressures. We allowed for heterogeneity in the substitution process and specifically tested for intersubtype recombination using Bayes factors. We also developed a new class of priors to assess significance across a wide range of support for recombination in the data. We applied our method to three putative gag gene recombinants. HIV-1 isolate RW024 decisively supported recombination with an inferred parental heritage of AD and a COP 95% Bayesian credible interval of (1,152, 1,178) using the HXB2 numbering scheme. HIV-1 isolate VI557 barely supported recombination. HIV-1 isolate RF decisively rejected recombination as expected, given that the sequence is commonly used as a reference sequence for subtype B. We employed scaled regeneration quantile plots to assess convergence and found this approach convenient to use even for our variable dimensional model parameter space.

Algorithms↗

PubMed2002

Regulation of circulating soluble leptin receptor levels by gender, adiposity, sex steroids, and leptin: observational and interventional studies in humans.

Leptin is an adipocyte-secreted hormone important in energy homeostasis and diverse physiological processes. A circulating soluble form of the leptin receptor [soluble leptin receptor (sOB-R)] is the main leptin-binding protein and determinant of free leptin index (FLI), the presumed biologically active form of leptin. We performed observational and interventional studies to elucidate the regulation of sOB-R and FLI in humans. In a cross-sectional study (n = 118), leptin, gender, and adiposity were significant determinants of sOB-R. By multivariate analysis, estradiol (E2) and testosterone predict sOB-R, whereas insulin predicts leptin and FLI. In a frequent-sampling study (n = 6), sOB-R followed a significant circadian rhythm inverse to that of leptin, suggesting that leptin's biological activity may have an even more pronounced diurnal variation than originally thought. A 72-h fast in eight men decreased leptin levels by 80% and increased lymphocyte expression of leptin receptor mRNA and serum sOB-R levels by 100%. Physiological and pharmacological doses of recombinant-methionyl human leptin (rhLeptin) administered to fasted men prevented the fasting-induced increase of sOB-R levels, and pharmacological doses resulted in a decrease in sOB-R levels. These studies provide evidence that sOB-R is regulated by gender, adiposity, hormones, and rhLeptin administration. This may have important implications for the biological activity of leptin in disease states associated with abnormal leptin levels (e.g., obesity and anorexia nervosa).

Adolescent↗

PubMedDate not supplied

Early nodal response as a predictor for necessity of functional neck dissection after chemoradiation.

PURPOSE: Chemoradiation is increasingly becoming the standard of care for node-positive squamous cell cancer of the head and neck. Response to chemoradiation for clinically node-positive disease in the neck is often difficult to ascertain because clinical response may or may not be predictive of pathological response. This often leads to uncertainty about the necessity of a functional neck dissection after chemoradiation. In this study, we retrospectively analyzed a cohort of node-positive patients to examine pathological response as well as clinical outcome after chemoradiation with or without functional neck dissection. METHODS: Using the radiation oncology records from 1993 until 2003, a population of 420 patients with squamous cell cancer of the head and neck were identified. Of these, 34 patients were clinically node positive at the time of diagnosis and under went chemoradiation as their primary therapy. All patients received a concurrent platinum-based regimen. Median radiation dose to gross neck disease was 68.4 Gy (range: 50.4-73.8 Gy). RESULTS: Median follow-up time was 25 months (range: 4-88 months). Patients with a complete response (17/34, 50%) after receiving 50 Gy finished the full course of therapy but did not undergo functional neck dissection. Only one patient (1/17) in this observation group experienced relapse in the neck. Patients with a partial response who received 50 Gy (17/34) completed therapy and under went functional neck dissection, regardless of response at the end of therapy. Fifty percent (3/6) with positive pathology had a regional relapse in the neck, whereas only 1/11 patients with negative pathology relapsed in the neck. This result compared favorably with those who were observed after chemoradiation. CONCLUSIONS: Clinical response at 50 Gy can be an effective means of selecting patients for functional neck dissection. Patients with complete response at 50 Gy may be observed with a low regional recurrence rate. Those patients with a partial response should undergo adjuvant neck dissection.

Antineoplastic Combined Chemotherapy Protocols↗