Dose optimisation with simultaneous pharmacokinetic estimation in adaptive clinical trials

2019 ◽  
Vol 29 (4) ◽  
pp. 1149-1166
Author(s):  
Kabir Soeny ◽  
Barbara Bogacka ◽  
Byron Jones
Keyword(s):  
Dose Regimen ◽  
Developmental Process ◽  
Cost Effective ◽  
Optimal Dose ◽  
Optimal Time ◽  
Model Parameters ◽  
Stage Design ◽  
Effective Manner ◽  
Dose Optimisation ◽  
Suboptimal Dose

Determination of the optimal dose is a critical objective in the drug developmental process. An optimal dose prevents over- and under-exposure to the treatment drug thereby facilitating superior patient experience and reduced costs to the healthcare system. In this paper, we present a method for model-based dose optimisation with simultaneous pharmacokinetic estimation of the model parameters. Multiple doses of the drug are considered and the objective is to maintain the blood concentration of the drug around a pre-decided target concentration. We consider an adaptive setting wherein the model parameters are estimated from the blood samples collected at D-optimal time points from all subjects enrolled so far in the trial. The estimated parameters are then used to determine the optimal dose regimen for the next cohort. This procedure continues until the condition of a pre-decided stopping rule is met. Simulation studies and sensitivity analysis are undertaken to validate the methodology. We also evaluate the performance of the methodology when carried out in a non-adaptive setting. A two-stage design is then presented which combines the advantages of the adaptive as well as the non-adaptive approach. We demonstrate that our methodology enables pharmacokinetic estimation and dose regimen optimisation simultaneously in an ethical and cost-effective manner protecting the subjects from the ill-effects of suboptimal dose regimens and economising the number of subjects required in the trial.

scholarly journals Cost-effective surveillance of invasive species using info-gap theory

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yang Liu ◽  
Penghao Wang ◽  
Melissa L. Thomas ◽  
Dan Zheng ◽  
Simon J. McKirdy
Keyword(s):  
Invasive Species ◽  
Native Species ◽  
Cost Effective ◽  
Expert Assessment ◽  
Parameter Estimates ◽  
Model Parameters ◽  
Surveillance Systems ◽  
Effective Manner ◽  
Novel Method ◽  
Population Threshold

AbstractInvasive species can lead to community-level damage to the invaded ecosystem and extinction of native species. Most surveillance systems for the detection of invasive species are developed based on expert assessment, inherently coming with a level of uncertainty. In this research, info-gap decision theory (IGDT) is applied to model and manage such uncertainty. Surveillance of the Asian House Gecko, Hemidactylus frenatus Duméril and Bibron, 1836 on Barrow Island, is used as a case study. Our research provides a novel method for applying IGDT to determine the population threshold ($$K$$ K ) so that the decision can be robust to the deep uncertainty present in model parameters. We further robust-optimize surveillance costs rather than minimize surveillance costs. We demonstrate that increasing the population threshold for detection increases both robustness to the errors in the model parameter estimates, and opportuneness to lower surveillance costs than the accepted maximum budget. This paper provides guidance for decision makers to balance robustness and required surveillance expenditure. IGDT offers a novel method to model and manage the uncertainty prevalent in biodiversity conservation practices and modelling. The method outlined here can be used to design robust surveillance systems for invasive species in a wider context, and to better tackle uncertainty in protection of biodiversity and native species in a cost-effective manner.

Strategic planning in grassland farming: Principles andapplications

1997 ◽  
pp. 191-197
Author(s):  
W.J. Parker ◽  
N.M. Shadbolt ◽  
D.I. Gray
Keyword(s):  
Strategic Planning ◽  
Performance Indicators ◽  
Cost Effective ◽  
Key Performance Indicators ◽  
Strategic Plans ◽  
Effective Manner ◽  
Farm Business ◽  
Pastoral Farming ◽  
Financial Environment

Three levels of planning can be distinguished in grassland farming: strategic, tactical and operational. The purpose of strategic planning is to achieve a sustainable long-term fit of the farm business with its physical, social and financial environment. In pastoral farming, this essentially means developing plans that maximise and best match pasture growth with animal demand, while generating sufficient income to maintain or enhance farm resources and improvements, and attain personal and financial goals. Strategic plans relate to the whole farm business and are focused on the means to achieve future needs. They should be routinely (at least annually) reviewed and monitored for effectiveness through key performance indicators (e.g., Economic Farm Surplus) that enable progress toward goals to be measured in a timely and cost-effective manner. Failure to link strategy with control is likely to result in unfulfilled plans. Keywords: management, performance

scholarly journals Novel Regeneration Approach for Creating Reusable FO-SPR Probes with NTA Surface Chemistry

Nanomaterials ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 186
Author(s):  
Jia-Huan Qu ◽  
Karen Leirs ◽  
Remei Escudero ◽  
Žiga Strmšek ◽  
Roman Jerala ◽  
...  
Keyword(s):  
Surface Chemistry ◽  
Fluorescent Protein ◽  
Cost Effective ◽  
Nitrilotriacetic Acid ◽  
Antibody Fragments ◽  
Rapid Screening ◽  
Red Fluorescent Protein ◽  
Effective Manner ◽  
Surface Regeneration ◽  
Sensitivity Specificity

To date, surface plasmon resonance (SPR) biosensors have been exploited in numerous different contexts while continuously pushing boundaries in terms of improved sensitivity, specificity, portability and reusability. The latter has attracted attention as a viable alternative to disposable biosensors, also offering prospects for rapid screening of biomolecules or biomolecular interactions. In this context here, we developed an approach to successfully regenerate a fiber-optic (FO)-SPR surface when utilizing cobalt (II)-nitrilotriacetic acid (NTA) surface chemistry. To achieve this, we tested multiple regeneration conditions that can disrupt the NTA chelate on a surface fully saturated with His6-tagged antibody fragments (scFv-33H1F7) over ten regeneration cycles. The best surface regeneration was obtained when combining 100 mM EDTA, 500 mM imidazole and 0.5% SDS at pH 8.0 for 1 min with shaking at 150 rpm followed by washing with 0.5 M NaOH for 3 min. The true versatility of the established approach was proven by regenerating the NTA surface for ten cycles with three other model system bioreceptors, different in their size and structure: His6-tagged SARS-CoV-2 spike fragment (receptor binding domain, RBD), a red fluorescent protein (RFP) and protein origami carrying 4 RFPs (Tet12SN-RRRR). Enabling the removal of His6-tagged bioreceptors from NTA surfaces in a fast and cost-effective manner can have broad applications, spanning from the development of biosensors and various biopharmaceutical analyses to the synthesis of novel biomaterials.

scholarly journals Postnatal management of children with antenatal hydronephrosis

2020 ◽  
Vol 26 (1) ◽  
Author(s):  
Mohammed S. ElSheemy
Keyword(s):  
Renal Function ◽  
Urinary Tract Obstruction ◽  
Cost Effective ◽  
Voiding Cystourethrography ◽  
Main Body ◽  
Antenatal Hydronephrosis ◽  
Postnatal Management ◽  
Effective Manner ◽  
Lower Urinary Tract Obstruction

Abstract Background Postnatal management of infants with antenatal hydronephrosis (ANH) is still one of the most controversial issues. The majority of infants with ANH are asymptomatic with only few children who develop renal insufficiency. Thus, the biggest challenge for pediatric urologists is to distinguish children who will require further investigations and possible intervention prior to the development of symptoms, complications or renal damage in a cost effective manner without exposing them to the hazards of unnecessary investigations. Main body In this review article, literature on ANH were reviewed to present the current suggestions, recommendations, guidelines and their rational for postnatal management of ANH. It is agreed that a large portion of infants with ANH will improve; thus, the protocol of management is based mainly on observation and follow-up by ultrasound to detect either resolution, stabilization or worsening of hydronephrosis. The first 2 years of life are critical for this follow-up as the final picture is mostly reached during that period. Advanced imaging using voiding cystourethrography or renal scintigraphy are required for children at risk. Then, surgical intervention is selected only for a subgroup of these infants who showed worsening of hydronephrosis or renal function. Conclusions The protocol of management is based mainly on observation and follow-up by US to detect either resolution, stabilization or worsening of hydronephrosis. Postnatal evaluation should be performed for any neonate with a history ANH at any stage during pregnancy even if it was resolved during third trimester. Exclusion of UTI should be performed by urinalysis for all cases followed by urine culture if indicated. Serum creatinine should be performed especially in patients with bilateral ANH. US is the initial standard diagnostic imaging technique. Other imaging modalities like VCUG and nuclear renal scans may be required according to the results of the US evaluation. The most important items in decision making are the presence of bilateral or unilateral hydronephrosis, presence or absence of hydroureter, presence of lower urinary tract obstruction and degree of hydronephrosis on the initial postnatal US. Then an intervention is selected only for a subgroup of these patients who showed deterioration in renal function or degree of hydronephrosis or were complicated by UTIs. All these recommendations are based on the available literature. However, management of ANH is still a controversial issue due to lack of high evidence-based recommendations. Randomised controlled studies are still needed to provide a high level evidence for different aspects of management.

scholarly journals Cost-effectiveness of TAS-102 plus bevacizumab versus TAS-102 monotherapy in patients with metastatic colorectal cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kiyoaki Sugiura ◽  
Yuki Seo ◽  
Takayuki Takahashi ◽  
Hideyuki Tokura ◽  
Yasuhiro Ito ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Health Care ◽  
Sensitivity Analysis ◽  
Cost Effectiveness ◽  
Combination Therapy ◽  
Metastatic Colorectal Cancer ◽  
Cost Effective ◽  
Model Parameters ◽  
Combination Regimen ◽  
The Cost

Abstract Background TAS-102 plus bevacizumab is an anticipated combination regimen for patients who have metastatic colorectal cancer. However, evidence supporting its use for this indication is limited. We compared the cost-effectiveness of TAS-102 plus bevacizumab combination therapy with TAS-102 monotherapy for patients with chemorefractory metastatic colorectal cancer. Method Markov decision modeling using treatment costs, disease-free survival, and overall survival was performed to examine the cost-effectiveness of TAS-102 plus bevacizumab combination therapy and TAS-102 monotherapy. The Japanese health care payer’s perspective was adopted. The outcomes were modeled on the basis of published literature. The incremental cost-effectiveness ratio (ICER) between the two treatment regimens was the primary outcome. Sensitivity analysis was performed and the effect of uncertainty on the model parameters were investigated. Results TAS-102 plus bevacizumab had an ICER of $21,534 per quality-adjusted life-year (QALY) gained compared with TAS-102 monotherapy. Sensitivity analysis demonstrated that TAS-102 monotherapy was more cost-effective than TAS-102 and bevacizumab combination therapy at a willingness-to-pay of under $50,000 per QALY gained. Conclusions TAS-102 and bevacizumab combination therapy is a cost-effective option for patients who have metastatic colorectal cancer in the Japanese health care system.

scholarly journals An Artificial-Intelligence-Discovered Functional Ingredient, NRT_N0G5IJ, Derived from Pisum sativum, Decreases HbA1c in a Prediabetic Population

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1635
Author(s):  
Sweeny Chauhan ◽  
Alish Kerr ◽  
Brian Keogh ◽  
Stephanie Nolan ◽  
Rory Casey ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Pisum Sativum ◽  
Cost Effective ◽  
Glycated Haemoglobin ◽  
Glucose Regulation ◽  
Functional Ingredient ◽  
Effective Manner ◽  
Human Skeletal Muscle Cells ◽  
Increased Risk

The prevalence of prediabetes is rapidly increasing, and this can lead to an increased risk for individuals to develop type 2 diabetes and associated diseases. Therefore, it is necessary to develop nutritional strategies to maintain healthy glucose levels and prevent glucose metabolism dysregulation in the general population. Functional ingredients offer great potential for the prevention of various health conditions, including blood glucose regulation, in a cost-effective manner. Using an artificial intelligence (AI) approach, a functional ingredient, NRT_N0G5IJ, was predicted and produced from Pisum sativum (pea) protein by hydrolysis and then validated. Treatment of human skeletal muscle cells with NRT_N0G5IJ significantly increased glucose uptake, indicating efficacy of this ingredient in vitro. When db/db diabetic mice were treated with NRT_N0G5IJ, we observed a significant reduction in glycated haemoglobin (HbA1c) levels and a concomitant benefit on fasting glucose. A pilot double-blinded, placebo controlled human trial in a population of healthy individuals with elevated HbA1c (5.6% to 6.4%) showed that HbA1c percentage was significantly reduced when NRT_N0G5IJ was supplemented in the diet over a 12-week period. Here, we provide evidence of an AI approach to discovery and demonstrate that a functional ingredient identified using this technology could be used as a supplement to maintain healthy glucose regulation.

scholarly journals Spectroscopic detection of forest diseases: a review (1970–2020)

2021 ◽  
Author(s):  
Lorenzo Cotrozzi
Keyword(s):  
Early Detection ◽  
Optical Sensors ◽  
Near Infrared ◽  
Sustainable Forest Management ◽  
Visible Spectrum ◽  
Cost Effective ◽  
Infrared Region ◽  
Forest Disturbances ◽  
Effective Manner ◽  
Forest Diseases

AbstractSustainable forest management is essential to confront the detrimental impacts of diseases on forest ecosystems. This review highlights the potential of vegetation spectroscopy in improving the feasibility of assessing forest disturbances induced by diseases in a timely and cost-effective manner. The basic concepts of vegetation spectroscopy and its application in phytopathology are first outlined then the literature on the topic is discussed. Using several optical sensors from leaf to landscape-level, a number of forest diseases characterized by variable pathogenic processes have been detected, identified and quantified in many country sites worldwide. Overall, these reviewed studies have pointed out the green and red regions of the visible spectrum, the red-edge and the early near-infrared as the spectral regions most sensitive to the disease development as they are mostly related to chlorophyll changes and symptom development. Late disease conditions particularly affect the shortwave-infrared region, mostly related to water content. This review also highlights some major issues to be addressed such as the need to explore other major forest diseases and geographic areas, to further develop hyperspectral sensors for early detection and discrimination of forest disturbances, to improve devices for remote sensing, to implement long-term monitoring, and to advance algorithms for exploitation of spectral data. Achieving of these goals will enhance the capability of vegetation spectroscopy in early detection of forest stress and in managing forest diseases.

scholarly journals To Trade or Not To Trade? Criteria for Applying Cap and Trade

2001 ◽  
Vol 1 ◽  
pp. 953-957 ◽  
Author(s):  
Stephanie Benkovic ◽  
Joseph Kruger
Keyword(s):  
Emissions Trading ◽  
Environmental Problem ◽  
Cost Effective ◽  
Cap And Trade ◽  
Policy Tool ◽  
Effective Manner ◽  
Effective Policy ◽  
Foreign Governments ◽  
Trading Program ◽  
The U.S

The use of emissions trading (cap and trade) is gaining worldwide recognition as an extremely effective policy tool. The U.S. Sulfur Dioxide (SO2) Emissions Trading Program has achieved an unprecedented level of environmental protection in a cost-effective manner. The successful results of the program have led domestic and foreign governments to consider the application of cap and trade to address other air quality issues. Certain analyses are particularly important in determining whether or not cap and trade is an appropriate policy tool. This paper offers a set of questions that can be used as criteria for determining whether or not cap and trade is the preferred policy approach to an environmental problem.

MANAGING GALLBLADDER DISEASE IN A COST-EFFECTIVE MANNER

1996 ◽  
Vol 76 (1) ◽  
pp. 117-128 ◽  
Author(s):  
Rocco Orlando ◽  
John C. Russell
Keyword(s):  
Gallbladder Disease ◽  
Cost Effective ◽  
Effective Manner
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