scholarly journals A Bayesian Adaptive Design in Cancer Phase I Trials Using Dose Combinations with Ordinal Toxicity Grades

Stats ◽  
2020 ◽  
Vol 3 (3) ◽  
pp. 221-238
Author(s):  
Márcio A. Diniz ◽  
Sungjin Kim ◽  
Mourad Tighiouart
Keyword(s):  
Adaptive Design ◽  
Parametric Models ◽  
Model Parameters ◽  
Operating Characteristics ◽  
Bayesian Adaptive Design ◽  
Continual Reassessment ◽  
Proportional Odds Assumption ◽  
Dose Combination ◽  
The One ◽  
The Relationship

We propose a Bayesian adaptive design for early phase drug combination cancer trials incorporating ordinal grade of toxicities. Parametric models are used to describe the relationship between the dose combinations and the probabilities of the ordinal toxicities under the proportional odds assumption. Trial design proceeds by treating cohorts of two patients simultaneously receiving different dose combinations. Specifically, at each stage of the trial, we seek the dose of one agent by minimizing the Bayes risk with respect to a loss function given the current dose of the other agent. We consider two types of loss functions corresponding to the Continual Reassessment Method (CRM) and Escalation with Overdose Control (EWOC). At the end of the trial, we estimate the MTD curve as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD by comparing this design to the one that uses a binary indicator of DLT. The methodology is further adapted to the case of a pre-specified discrete set of dose combinations.

scholarly journals A Bayesian Adaptive Design in Cancer Phase I Trials Using Dose Combinations in the Presence of a Baseline Covariate

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Márcio Augusto Diniz ◽  
Sungjin Kim ◽  
Mourad Tighiouart
Keyword(s):  
Phase I ◽  
Adaptive Design ◽  
Cytotoxic Agents ◽  
Dose Finding ◽  
Model Parameters ◽  
Baseline Characteristic ◽  
Phase I Clinical Trials ◽  
Bayesian Adaptive Design ◽  
Dose Combination ◽  
Toxicity Relationship

A Bayesian adaptive design for dose finding of a combination of two drugs in cancer phase I clinical trials that takes into account patients heterogeneity thought to be related to treatment susceptibility is described. The estimation of the maximum tolerated dose (MTD) curve is a function of a baseline covariate using two cytotoxic agents. A logistic model is used to describe the relationship between the doses, baseline covariate, and the probability of dose limiting toxicity (DLT). Trial design proceeds by treating cohorts of two patients simultaneously using escalation with overdose control (EWOC), where at each stage of the trial, the next dose combination corresponds to the α quantile of the current posterior distribution of the MTD of one of two agents at the current dose of the other agent and the next patient’s baseline covariate value. The MTD curves are estimated as function of Bayes estimates of the model parameters at the end of trial. Average DLT, pointwise average bias, and percent of dose recommendation at dose combination neighborhoods around the true MTD are compared between the design that uses the covariate and the one that ignores the baseline characteristic. We also examine the performance of the approach under model misspecifications for the true dose-toxicity relationship. The methodology is further illustrated in the case of a prespecified discrete set of dose combinations.

scholarly journals Bayesian Adaptive Design for Finding the Maximum Tolerated Sequence of Doses in Multicycle Dose-Finding Clinical Trials

2018 ◽  
pp. 1-19 ◽  
Author(s):  
Jiaying Lyu ◽  
Emily Curran ◽  
Yuan Ji
Keyword(s):  
Adaptive Design ◽  
Decision Rules ◽  
Dose Finding ◽  
Patient Specific ◽  
Precision Oncology ◽  
Operating Characteristics ◽  
Time Saving ◽  
Bayesian Adaptive Design ◽  
Statistical Designs ◽  
Dosing Strategy

Purpose Statistical designs for traditional phase I dose-finding trials consider dose-limiting toxicity in the first cycle of treatment. In reality, patients often go through multiple cycles of treatment and may experience toxicity events in more than one cycle. Therefore, it is desirable to identify the maximum tolerated sequence of three doses across three cycles of treatment. Methods Motivated by a three-cycle dose-finding clinical trial for a rare cancer with a JAK inhibitor, we proposed and implemented a simple Bayesian adaptive dose-cycle finding (BaSyc) design that allows intercycle and intrapatient dose modification. Because of the patient-specific dosing strategy over cycles, the BaSyc design is suited as a method in precision oncology. Results BaSyc is simple and transparent because its algorithm can be summarized as two tabulated decision rules before the trial starts, allowing physicians to visually examine these rules. In addition, BaSyc employs a time-saving enrollment scheme that speeds up the trial. Extensive simulation studies show that BaSyc has desirable operating characteristics in identifying the maximum tolerated sequence. Conclusion The BaSyc design provides a first-of-kind multicycle approach for dose finding and will likely lead to better and safer patient care and drug development.

scholarly journals Prediction of Repeat-Dose Occupancy from Single-Dose Data: Characterisation of the Relationship between Plasma Pharmacokinetics and Brain Target Occupancy

2010 ◽  
Vol 31 (3) ◽  
pp. 944-952 ◽  
Author(s):  
Sergio Abanades ◽  
Jasper van der Aart ◽  
Julien AR Barletta ◽  
Carmine Marzano ◽  
Graham E Searle ◽  
...  
Keyword(s):  
Single Dose ◽  
Drug Development ◽  
Time Course ◽  
Adaptive Design ◽  
Model Parameters ◽  
Repeat Dose ◽  
Dose Selection ◽  
Direct Model ◽  
Brain Target ◽  
The Relationship

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [11C]DASB ([11C] N, N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50=2.62±0.93 ng/mL) was significantly better ( P<0.05) than that from the direct model (OC50=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD.

Pilot Slasher Yarn Drying Model Identification

1988 ◽  
Vol 58 (1) ◽  
pp. 27-34 ◽  
Author(s):  
Allen M. Haas ◽  
Morton W. Reed ◽  
Dennis C. Williams
Keyword(s):  
Steady State ◽  
Model Identification ◽  
Model Parameters ◽  
Operating Characteristics ◽  
First Order ◽  
Percent Moisture ◽  
Basic Operating ◽  
On Line ◽  
Drying Model ◽  
The Relationship

The steady state and dynamic response of a pilot slasher were investigated. Continuous on-line recording of moisture was used to determine the response of the exit moisture to step changes in yarn speed. A method to determine the drying rate from steady state data was developed, and a model describing the relationship between yarn speed and percent moisture regain was proposed and evaluated. The model consists of two first order systems acting in parallel, where the model parameters are functions of yarn speed. This work points out basic operating characteristics of pilot and industrial slashers.

Misreading Egypt

2018 ◽  
Author(s):  
Jesse Schotter
Keyword(s):  
New Media ◽  
Narrative Form ◽  
Experimental Film ◽  
Tower Of Babel ◽  
Avant Garde ◽  
Sergei Eisenstein ◽  
History Of ◽  
The One ◽  
The Relationship ◽  
Modern Technologies

The first chapter of Hieroglyphic Modernisms exposes the complex history of Western misconceptions of Egyptian writing from antiquity to the present. Hieroglyphs bridge the gap between modern technologies and the ancient past, looking forward to the rise of new media and backward to the dispersal of languages in the mythical moment of the Tower of Babel. The contradictory ways in which hieroglyphs were interpreted in the West come to shape the differing ways that modernist writers and filmmakers understood the relationship between writing, film, and other new media. On the one hand, poets like Ezra Pound and film theorists like Vachel Lindsay and Sergei Eisenstein use the visual languages of China and of Egypt as a more primal or direct alternative to written words. But Freud, Proust, and the later Eisenstein conversely emphasize the phonetic qualities of Egyptian writing, its similarity to alphabetical scripts. The chapter concludes by arguing that even avant-garde invocations of hieroglyphics depend on narrative form through an examination of Hollis Frampton’s experimental film Zorns Lemma.

Researching (with) Major Food Retailers

2015 ◽  
Vol 15 (3) ◽  
pp. 33-39 ◽  
Author(s):  
David Evans
Keyword(s):  
Food Systems ◽  
Academic Research ◽  
Social Scientists ◽  
Major Food ◽  
Food Retailers ◽  
Food Retailer ◽  
The One ◽  
The Uk ◽  
The Relationship ◽  
Opening Up

This paper considers the relationship between social science and the food industry, and it suggests that collaboration can be intellectually productive and morally rewarding. It explores the middle ground that exists between paid consultancy models of collaboration on the one hand and a principled stance of nonengagement on the other. Drawing on recent experiences of researching with a major food retailer in the UK, I discuss the ways in which collaborating with retailers can open up opportunities for accessing data that might not otherwise be available to social scientists. Additionally, I put forward the argument that researchers with an interest in the sustainability—ecological or otherwise—of food systems, especially those of a critical persuasion, ought to be empirically engaging with food businesses. I suggest that this is important in terms of generating better understandings of the objectionable arrangements that they seek to critique, and in terms of opening up conduits through which to affect positive changes. Cutting across these points is the claim that while resistance to commercial engagement might be misguided, it is nevertheless important to acknowledge the power-geometries of collaboration and to find ways of leveling and/or leveraging them. To conclude, I suggest that universities have an important institutional role to play in defining the terms of engagement as well as maintaining the boundaries between scholarship and consultancy—a line that can otherwise become quite fuzzy when the worlds of commerce and academic research collide.

Choice Of Technique And The Volume Of Saving (A Re-Examination Of The Cobb-Douglas Model)

1968 ◽  
Vol 8 (4) ◽  
pp. 606-617
Author(s):  
Mohammad Anisur Rahman
Keyword(s):  
Economic Development ◽  
Production Function ◽  
Development Policy ◽  
Social Goals ◽  
The Other ◽  
Economic Development Policy ◽  
Labour Intensity ◽  
The One ◽  
Choice Of Technique ◽  
The Relationship

The purpose of this paper is to re-examine the relationship between the degree of aggregate labour-intensity and the aggregate volume of saving in an economy where a Cobb-6ouglas production function in its traditional form can be assumed to give a good approximation to reality. The relationship in ques¬tion has an obviously important bearing on economic development policy in the area of choice of labour intensity. To the extent that and in the range where an increase in labour intensity would adversely affect the volume of savings, a con¬flict arises between two important social objectives, i.e., higher rate of capital formation on the one hand and greater employment and distributive equity on the other. If relative resource endowments in the economy are such that such a "competitive" range of labour-intensity falls within the nation's attainable range of choice, development planners will have to arrive at a compromise between these two social goals.

Constructing and model-fitting receiver operator characteristics using continuous data.

2018 ◽  
Author(s):  
Josephine Ann Urquhart ◽  
Akira O'Connor
Keyword(s):  
Signal Detection ◽  
Least Squares Method ◽  
Model Fitting ◽  
Simulated Data ◽  
Continuous Variable ◽  
Continuous Data ◽  
Model Parameters ◽  
Operating Characteristics ◽  
Unequal Variance ◽  
Discrete Discrimination

Receiver operating characteristics (ROCs) are plots which provide a visual summary of a classifier’s decision response accuracy at varying discrimination thresholds. Typical practice, particularly within psychological studies, involves plotting an ROC from a limited number of discrete thresholds before fitting signal detection parameters to the plot. We propose that additional insight into decision-making could be gained through increasing ROC resolution, using trial-by-trial measurements derived from a continuous variable, in place of discrete discrimination thresholds. Such continuous ROCs are not yet routinely used in behavioural research, which we attribute to issues of practicality (i.e. the difficulty of applying standard ROC model-fitting methodologies to continuous data). Consequently, the purpose of the current article is to provide a documented method of fitting signal detection parameters to continuous ROCs. This method reliably produces model fits equivalent to the unequal variance least squares method of model-fitting (Yonelinas et al., 1998), irrespective of the number of data points used in ROC construction. We present the suggested method in three main stages: I) building continuous ROCs, II) model-fitting to continuous ROCs and III) extracting model parameters from continuous ROCs. Throughout the article, procedures are demonstrated in Microsoft Excel, using an example continuous variable: reaction time, taken from a single-item recognition memory. Supplementary MATLAB code used for automating our procedures is also presented in Appendix B, with a validation of the procedure using simulated data shown in Appendix C.

Bastard Feudalism and the Framing of Thirteenth-Century England

2018 ◽  
Author(s):  
Peter Coss
Keyword(s):  
Middle Ages ◽  
Thirteenth Century ◽  
Twelfth Century ◽  
The State ◽  
The Other ◽  
Great Work ◽  
Early Middle Ages ◽  
The One ◽  
The Relationship

In the introduction to his great work of 2005, Framing the Early Middle Ages, Chris Wickham urged not only the necessity of carefully framing our studies at the outset but also the importance of closely defining the words and concepts that we employ, the avoidance ‘cultural sollipsism’ wherever possible and the need to pay particular attention to continuities and discontinuities. Chris has, of course, followed these precepts on a vast scale. My aim in this chapter is a modest one. I aim to review the framing of thirteenth-century England in terms of two only of Chris’s themes: the aristocracy and the state—and even then primarily in terms of the relationship between the two. By the thirteenth century I mean a long thirteenth century stretching from the period of the Angevin reforms of the later twelfth century on the one hand to the early to mid-fourteenth on the other; the reasons for taking this span will, I hope, become clearer during the course of the chapter, but few would doubt that it has a validity.

scholarly journals A New Paradigm in the Relationship between Melatonin and Breast Cancer: Gut Microbiota Identified as a Potential Regulatory Agent

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3141
Author(s):  
Aurora Laborda-Illanes ◽  
Lidia Sánchez-Alcoholado ◽  
Soukaina Boutriq ◽  
Isaac Plaza-Andrades ◽  
Jesús Peralta-Linero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gut Microbiota ◽  
Bacterial Population ◽  
Kynurenine Pathway ◽  
New Paradigm ◽  
Bacterial Composition ◽  
Glucuronidase Activity ◽  
The One ◽  
The Relationship ◽  
Melatonin Production

In this review we summarize a possible connection between gut microbiota, melatonin production, and breast cancer. An imbalance in gut bacterial population composition (dysbiosis), or changes in the production of melatonin (circadian disruption) alters estrogen levels. On the one hand, this may be due to the bacterial composition of estrobolome, since bacteria with β-glucuronidase activity favour estrogens in a deconjugated state, which may ultimately lead to pathologies, including breast cancer. On the other hand, it has been shown that these changes in intestinal microbiota stimulate the kynurenine pathway, moving tryptophan away from the melatonergic pathway, thereby reducing circulating melatonin levels. Due to the fact that melatonin has antiestrogenic properties, it affects active and inactive estrogen levels. These changes increase the risk of developing breast cancer. Additionally, melatonin stimulates the differentiation of preadipocytes into adipocytes, which have low estrogen levels due to the fact that adipocytes do not express aromatase. Consequently, melatonin also reduces the risk of breast cancer. However, more studies are needed to determine the relationship between microbiota, melatonin, and breast cancer, in addition to clinical trials to confirm the sensitizing effects of melatonin to chemotherapy and radiotherapy, and its ability to ameliorate or prevent the side effects of these therapies.

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