Analysis Of Dose-response Data Research Articles

Immunologic Dose-Response to Adenovirus-Vectored Vaccines in Animals and Humans: A Systematic Review of Dose-Response Studies of Replication Incompetent Adenoviral Vaccine Vectors when Given via an Intramuscular or Subcutaneous Route.

Optimal vaccine dosing is important to ensure the greatest protection and safety. Analysis of dose-response data, from previous studies, may inform future studies to determine the optimal dose. Implementing more quantitative modelling approaches in vaccine dose finding have been recently suggested to accelerate vaccine development. Adenoviral vectored vaccines are in advanced stage of development for a variety of prophylactic and therapeutic indications, however dose-response has not yet been systematically determined. To further inform adenoviral vectored vaccines dose identification, historical dose-response data should be systematically reviewed. A systematic literature review was conducted to collate and describe the available dose-response studies for adenovirus vectored vaccines. Of 2787 papers identified by Medline search strategy, 35 were found to conform to pre-defined criteria. The majority of studies were in mice or humans and studied adenovirus serotype 5. Dose-response data were available for 12 different immunological responses. The majority of papers evaluated three dose levels, only two evaluated more than five dose levels. The most common dosing range was 107–1010 viral particles in mouse studies and 108–1011 viral particles in human studies. Data were available on adenovirus vaccine dose-response, primarily on adenovirus serotype 5 backbones and in mice and humans. These data could be used for quantitative adenoviral vectored vaccine dose optimisation analysis.

A TaqMan® Reverse Transcription Polymerase Chain Reaction (RT-PCR) In Vitro Potency Assay for Plasmid-based Vaccine Products

A TaqMan-based reverse transcription polymerase chain reaction (RT-PCR) assay has been developed as an in vitro potency assay to measure the most immediate biological activity of plasmid DNA (pDNA)-based products. The assay measures transgene-specific messenger RNA (mRNA) from cultured cells transfected with VCL-CB01, a bivalent pDNA-based human cytomegalovirus (CMV) vaccine. The forward and reverse primers have been designed to make the RT-PCR reaction selective for plasmid-derived mRNA and to allow discrimination of expression levels of individual plasmids in a multivalent pDNA vaccine. The relative potency of a vaccine lot is assessed by transfecting reference and test samples into cultured cells in parallel and analyzing total RNA from the cells by RT-PCR. Statistical analysis of dose response data from reference material supports a parallel-line model for calculating relative potency. Preliminary data demonstrate the ability of this assay to distinguish product potencies at 50, 75, 150, and 200% of the reference material. In addition, forced degradation of pDNA demonstrates that a decrease in relative potency as measured by the RT-PCR assay in vitro correlates well with a decrease in CMV DNA vaccine-mediated humoral immune responses in mice injected with the same material.

BMDExpress: a software tool for the benchmark dose analyses of genomic data

BackgroundDose-dependent processes are common within biological systems and include phenotypic changes following exposures to both endogenous and xenobiotic molecules. The use of microarray technology to explore the molecular signals that underlie these dose-dependent processes has become increasingly common; however, the number of software tools for quantitatively analyzing and interpreting dose-response microarray data has been limited.ResultsWe have developed BMDExpress, a Java application that combines traditional benchmark dose methods with gene ontology classification in the analysis of dose-response data from microarray experiments. The software application is designed to perform a stepwise analysis beginning with a one-way analysis of variance to identify the subset of genes that demonstrate significant dose-response behavior. The second step of the analysis involves fitting the gene expression data to a selection of standard statistical models (linear, 2° polynomial, 3° polynomial, and power models) and selecting the model that best describes the data with the least amount of complexity. The model is then used to estimate the benchmark dose at which the expression of the gene significantly deviates from that observed in control animals. Finally, the software application summarizes the statistical modeling results by matching each gene to its corresponding gene ontology categories and calculating summary values that characterize the dose-dependent behavior for each biological process and molecular function. As a result, the summary values represent the dose levels at which genes in the corresponding cellular process show transcriptional changes.ConclusionThe application of microarray technology together with the BMDExpress software tool represents a useful combination in characterizing dose-dependent transcriptional changes in biological systems. The software allows users to efficiently analyze large dose-response microarray studies and identify reference doses at which particular cellular processes are altered. The software is freely available at and is distributed under the MIT Public License.

Fundamental form of a population TCP model in the limit of large heterogeneity

A population tumor control probability (TCP) model for fractionated external beam radiotherapy, based on Poisson statistics and in the limit of large parameter heterogeneity, is studied. A reduction of a general eight-parameter TCP equation, which incorporates heterogeneity in parameters characterizing linear-quadratic radiosensitivity, repopulation, and clonogen number, to an equation with four parameters is obtained. The four parameters represent the mean and standard deviation for both clonogen number and a generalized radiosensitivity that includes linear-quadratic and repopulation descriptors. Further, owing to parameter inter-relationship, it is possible to express these four parameters as three ratios of parameters in the large heterogeneity limit. These ratios can be directly linked to two defining features of the TCP dose response: D50 and gamma50. In the general case, the TCP model can be written in terms of D50, gamma50 and a third parameter indicating the ratio of the levels of heterogeneity in clonogen number and generalized radiosensitivity; however, the third parameter is unnecessary when either of these two sources of heterogeneity is dominant. It is shown that heterogeneity in clonogen number will have little impact on the TCP formula for clinical scenarios, and thus it will generally be the case that the fundamental form of the Poisson-based population TCP model can be specified completely in terms of D50 and gamma50: TCP= 1/2 erfc[square root of pi(gamma50)(D50/D-1)]. This implies that limited radiobiological information can be determined by the analysis of dose response data: information about parameter ratios can be ascertained, but knowledge of absolute values for the fundamental radiobiological parameters will require independent auxiliary measurements.

Insulin resistance in patients with colorectal cancer

The euglycaemic glucose clamp technique has been used to assess insulin resistance in patients with colorectal adenocarcinoma. Ten cancer patients were studied and compared with control subjects matched for age, sex and nutritional status. Forty-one euglycaemic clamps were performed at one of five different insulin infusion rates (20, 30, 40, 100 or 200 milliunits min-1 m-2). Glucose disposal was significantly decreased in the cancer group at all insulin infusion rates, whilst attained insulin levels and metabolic clearance rates of insulin were comparable in the control and cancer groups. Analysis of dose-response data allowed assessment of sensitivity (insulin concentration of half maximal glucose disposal) and responsiveness (maximal glucose disposal). Responsiveness was significantly reduced in the cancer group (40.3 versus 71.5 mumol kg-1 min-1; P less than 0.001), whilst sensitivity was similar (93.7 milliunits l-1 in controls versus 90.8 milliunits l-1 in cancer patients), suggesting a postreceptor defect in insulin action in the cancer group.

COMPARING ESTIMATION PROCEDURES FOR DOSE-RESPONSE FUNCTIONS

The dose-response design is often used in agricultural research when it is necessary to measure a biological response at various levels of an experimental factor. This type of problem is common in chemical and pesticide research, however, it can also occur in other disciplines such as plant, animal, soil, and environmental sciences. While the analysis of dose-response data usually involves fitting a regression curve, the primary objective often centers on the estimation of dose related percentiles such as the LD50 or LC50. These measures are useful for comparing the relative efficacy of various treatments, however, the estimation of the specified percentiles is not always straightforward. Traditional methodology has relied on inverted solutions or asymptotic theory for statistical inference. More recently, computer intensive methods have been used to model dose-response relationships and can be more appropriate than traditional methods in some situations. This paper examines both the traditional and modem approaches to estimating doseresponse functions as they apply to binomial data. The techniques will be demonstrated using mortality data collected on black vine weevil eggs exposed to an organic pesticide treatment.

Risk Assessment via a Robust Probit Model, with Application to Toxicology

Various frameworks have been suggested for assessing the risk associated with continuous toxicity outcomes. The first formulates the effect of exposure on the adverse effect via a simple normal model and then computes the risk function using tail probabilities from the standard normal distribution. Because this risk function depends heavily on the assumed model, it may be sensitive to model misspecification. Recently, a semiparametric approach that utilizes an alternative definition of excess risk has been studied. Unfortunately, it is not yet clear how the two approaches relate to one another. In this article, we investigate a semiparametric normal model in which an unknown transformation of the adverse response satisfies the linear model. We demonstrate that this formulation unifies the two existing approaches and allows for a coherent risk analysis of dose-response data. In addition, estimation and inference procedures for the unknown transformation in the semiparametric model for the continuous response are developed. These are incorporated in novel model-checking procedures, including a formal sup-norm test of the simple normal model. A well-known toxicological study of aconiazide, a drug under investigation for treatment of tuberculosis, serves as a case study for the risk assessment methodology.

The effects of noribogaine and harmaline in rats trained with ibogaine as a discriminative stimulus

In the present investigation, Fischer-344 rats were trained to discriminate 10.0 mg/kg of ibogaine from water using a pretreatment time of 60 minutes. Analysis of dose response data generated an ED50 of 4.6 mg/kg. The time course of the ibogaine (10.0 mg/kg) cue was also determined. The stimulus reached a maximum level of 94% ibogaine-appropriate responding at the 60-min pretreatment time. This was followed by a time-dependent decrease in ibogaine-appropriate responding. At a pretreatment time of 8 hrs only 6.4% drug-appropriate responding was observed. In substitution experiments, intermediate generalization was observed with a metabolite of ibogaine, 12-hydroxyibogamine [noribogaine] (71.6%) whereas complete generalization was seen with harmaline (83.5%).

Tail Functions and Iterative Weights in Binary Regression

Abstract In interpreting the binary regression models often used in the analysis of dose-response data, it is common to introduce the idea of an underlying continuous tolerance distribution. Different choices of link function lead to different tolerance distributions. A useful way of comparing these alternatives is to compare the hazard functions or tail functions associated with each tolerance distribution. Tail functions can also be applied to give numerically preferable formulas for the iterative weights and the adjusted dependent variable in the fitting of binary regression models by the iteratively reweighted least-squares algorithm.

Analysis of Dose-Response Data in the Presence of Extrabinomial Variation

SUMMARY Binary dose-response data often exhibit extrabinomial variation when the responses arise naturally in groups or litters. This paper investigates the use of generalized Wald and score statistics for robustifying the standard inference methods based on the binomial likelihood. Special attention is given to the probit analysis of a parallel assay of the teratogenic effects on mice of several dioxins.

Resistance or conductance for expression of arterial vascular tone

The traditional expression of vascular tone is resistance (pressure gradient/flow). It is shown that common manipulations of resistance data, such as arithmetic averaging or linear regression, can lead to substantial errors in situations where blood flow changes to a much greater extent than pressure gradient (the usual in vivo situation). These errors do not occur when conductance is used. Calculations of the extent of vascular escape from vasoconstrictor stimuli and analysis of dose-response data by classical pharmacodynamic methods can be used where such data are expressed as conductance but not when such data are expressed as resistance. Thus, vascular conductance best reflects vascular tone in situations where changes in tone lead primarily to changes in flow. Resistance is the appropriate index for a constant flow preparation, where changes in vascular tone lead primarily to changes in perfusion pressure gradient.

Mutagenesis and mathematics: the allure of numbers.

This paper sets out the "formal," "empirical," and "mechanistic" equations that my colleagues and I have developed for the description and analysis of dose-response data on the lethal and genetic effects of mutagens in microorganisms. These three types of equations are interrelated inasmuch as they are all based ultimately on the use of the Poisson distribution in the formal definition of lethal and mutational hit functions. Explicit mathematical expressions for these functions can be written down in either empirical or mechanistic terms. The empirical equations are obtained simply by writing the hit functions as finite polynomials with adjustable coefficients. The mechanistic equations are based on the assumptions of the "DNA damage-repair hypothesis." The mathematical formulation of this hypothesis entails an important change in the definition of the word "hit" from that used in the classical hit/target theory of radiation biology. The theoretical and practical applications of these various equations in mutation research are summarized briefly and their merits are assessed in light of recent advances in our understanding of the biochemical basis of mutagenesis.

Characteristics of hepatic receptors for somatomedin-C/insulin-like growth factor I and insulin in the developing human.

Insulin and the somatomedins (Sms) are putative regulators of cell proliferation and metabolism in the fetus. Since the liver is a potential target tissue of these hormones during fetal life, we characterized the hepatic receptors for Sm-C/insulin like growth factor I (Sm-C/IGF-I) and insulin during the second trimester of human fetal development. Membrane-enriched fetal liver homogenates specifically bound 8.9 +/- 1.5% (+/- SD) of added [125I]insulin and 5.1-7.2% of [125I]Sm-C/IGF-I. Binding of both hormones was constant from 12-20 weeks gestation and was much greater than that in adult liver membranes. Analysis of dose-response data indicated high affinity between each receptor and its respective ligand (Kd for the Sm-C/IGF-I receptor, 2.2 X 10(-10) M; Kd for insulin receptor, 5.2 X 10(-10) and 7.7 X 10(-9) M). Limited cross-reactivity (approximately 1:1,000) of insulin with the Sm-C/IGF-I receptor and Sm-C/IGF-I with the insulin receptor was found. Affinity labeling studies showed that each receptor possessed an approximately 135,000-dalton subunit which was a part of a larger disulfide-linked complex. Thus, the human fetal liver has specific receptors for Sm-C/IGF-I and insulin that are similar to those described for other tissues in terms of both hormone-binding characteristics and subunit structure, suggesting that these receptors mediate important cellular functions at this stage of fetal development.

Analysis of dose-response data in mutation research

Work on environmental transuranium nuclides at the Institute for Radiation Protection of the Gesellschaft für Strahlen- und Umweltforschung mbH, Munich, is briefly described and standard needs are discussed. Fallout plutonium measurements in air dust and precipitation samples started in 1970/1971. The procedure is outlined and results are presented as annual mean and sum values, respectively. Since 1973, transuranium nuclides in primary coolant, stack effluent air and waste-water samples from nuclear power stations are measured. Nuclides detected are 239/240Pu, 238Pu and/or 241Am, 242Cm and 244Cm. Examples of alpha particle spectra are given. Needs for standards in environmental transuranium analysis are discussed.

A model that leads to the Weibull distribution function to characterize early radiation response probabilities.

The probability of inducing a specific early radiation syndrome is characterized by using a model in which injury to a critical cluster of cells, from a large number of critical cell clusters at risk, is responsible for causing the syndrome. This model leads to a two parameter Weibull cumulative distribution function that represents the probability that a given radiation syndrome will be induced by an absorbed radiation dose to the critical cells at risk less than or equal to a given value. Results from an analysis of dose-response data after exposure to internal radiation sources suggest that the probability of inducing a given radiation syndrome depends on the absorbed radiation dose, dose rate and radiation quality. In the design of experiments to study late occurring effects of radiation (e.g. tumor induction), it is important to minimize the risk of acute deaths. For this reason, results presented in this manuscript can be used to design better late effects studies. The results can also be used in reactor hazard analysis.

The guinea pig tracheobronchial spiral strip: responses to selected agonists.

The guinea pig tracheal spiral strip is a useful preparation for studying bronchoconstrictor and bronchodilator compounds. Employing a simple and rapid modification of this technique, experiments were performed in vitro to quantitate the effects of selected bronchospastic agents on guinea pig tracheobronchial smooth muscle. Three sections of the main airways were prepared from each animal: an upper tracheal, a lower tracheal, and a bronchial segment. The dose-dependent contractile responses of the three tissue segments were determined for carbachol, acetylcholine, histamine, 5-hydroxytryptamine, and bradykinin. Differences were observed amongst the agonists in magnitudes of contraction, effective concentration ranges, and slopes of dose-response curves. ED25, ED50, and ED75 values were calculated from regression analysis of dose-response data. The relative order for these agents to produce maximum contractions was found to be carbachol congruent to acetylcholine greater than histamine greater than 5-hydroxytryptamine greater than bradykinin. Furthermore, it was found that there was no significant difference between the three tissue segments in their responses to the various agonists.

The role and action of environmental agents in the pathogenesis of hung cancer. I. Air pollutants.

The role and action of environmental agents in the pathogenesis of hung cancer. I. Air pollutants.

Comments on the Analysis of Dose-Response Data in Experimental Carcinogenesis

Comments on the Analysis of Dose-Response Data in Experimental Carcinogenesis

Induced Pulmonary Tumors in Mice. IV. Analysis of Dose Response Data with Methylcholanthrene

Induced Pulmonary Tumors in Mice. IV. Analysis of Dose Response Data with Methylcholanthrene

Quantitative Analysis of Dose-Response Data Obtained With Three Carcinogenic Hydrocarbons in Strain C3H Male Mice

Quantitative Analysis of Dose-Response Data Obtained With Three Carcinogenic Hydrocarbons in Strain C3H Male Mice