Development of musculoskeletal models for the design and the pre-clinical validation of hip resurfacing prosthesis

Background. The surgical treatment of dysfunctional hips is a severe condition for the patient and a costly therapy for the public health. Hip resurfacing techniques seem to hold the promise of various advantages over traditional THR, with particular attention to young and active patients. Although the lesson provided in the past by many branches of engineering is that success in designing competitive products can be achieved only by predicting the possible scenario of failure, to date the understanding of the implant quality is poorly pre-clinically addressed. Thus revision is the only delayed and reliable end point for assessment. The aim of the present work was to model the musculoskeletal system so as to develop a protocol for predicting failure of hip resurfacing prosthesis. Methods. Preliminary studies validated the technique for the generation of subject specific finite element (FE) models of long bones from Computed Thomography data. The proposed protocol consisted in the numerical analysis of the prosthesis biomechanics by deterministic and statistic studies so as to assess the risk of biomechanical failure on the different operative conditions the implant might face in a population of interest during various activities of daily living. Physiological conditions were defined including the variability of the anatomy, bone densitometry, surgery uncertainties and published boundary conditions at the hip. The protocol was tested by analysing a successful design on the market and a new prototype of a resurfacing prosthesis. Results. The intrinsic accuracy of models on bone stress predictions (RMSE < 10%) was aligned to the current state of the art in this field. The accuracy of prediction on the bone-prosthesis contact mechanics was also excellent (< 0.001 mm). The sensitivity of models prediction to uncertainties on modelling parameter was found below 8.4%. The analysis of the successful design resulted in a very good agreement with published retrospective studies. The geometry optimisation of the new prototype lead to a final design with a low risk of failure. The statistical analysis confirmed the minimal risk of the optimised design over the entire population of interest. The performances of the optimised design showed a significant improvement with respect to the first prototype (+35%). Limitations. On the authors opinion the major limitation of this study is on boundary conditions. The muscular forces and the hip joint reaction were derived from the few data available in the literature, which can be considered significant but hardly representative of the entire variability of boundary conditions the implant might face over the patients population. This moved the focus of the research on modelling the musculoskeletal system; the ongoing activity is to develop subject-specific musculoskeletal models of the lower limb from medical images. Conclusions. The developed protocol was able to accurately predict known clinical outcomes when applied to a well-established device and, to support the design optimisation phase providing important information on critical characteristics of the patients when applied to a new prosthesis. The presented approach does have a relevant generality that would allow the extension of the protocol to a large set of orthopaedic scenarios with minor changes. Hence, a failure mode analysis criterion can be considered a suitable tool in developing new orthopaedic devices.

Middleware principles and design for the integration of ubiquitos mobile services

Nowadays, in Ubiquitous computing scenarios users more and more require to exploit online contents and services by means of any device at hand, no matter their physical location, and by personalizing and tailoring content and service access to their own requirements. The coordinated provisioning of content tailored to user context and preferences, and the support for mobile multimodal and multichannel interactions are of paramount importance in providing users with a truly effective Ubiquitous support. However, so far the intrinsic heterogeneity and the lack of an integrated approach led to several either too vertical, or practically unusable proposals, thus resulting in poor and non-versatile support platforms for Ubiquitous computing. This work investigates and promotes design principles to help cope with these ever-changing and inherently dynamic scenarios. By following the outlined principles, we have designed and implemented a middleware support platform to support the provisioning of Ubiquitous mobile services and contents. To prove the viability of our approach, we have realized and stressed on top of our support platform a number of different, extremely complex and heterogeneous content and service provisioning scenarios. The encouraging results obtained are pushing our research work further, in order to provide a dynamic platform that is able to not only dynamically support novel Ubiquitous applicative scenarios by tailoring extremely diverse services and contents to heterogeneous user needs, but is also able to reconfigure and adapt itself in order to provide a truly optimized and tailored support for Ubiquitous service provisioning.

Uniquitous internet middleware: architecture design and prototype evaluation

Technology advances in recent years have dramatically changed the way users exploit contents and services available on the Internet, by enforcing pervasive and mobile computing scenarios and enabling access to networked resources almost from everywhere, at anytime, and independently of the device in use. In addition, people increasingly require to customize their experience, by exploiting specific device capabilities and limitations, inherent features of the communication channel in use, and interaction paradigms that significantly differ from the traditional request/response one. So-called Ubiquitous Internet scenario calls for solutions that address many different challenges, such as device mobility, session management, content adaptation, context-awareness and the provisioning of multimodal interfaces. Moreover, new service opportunities demand simple and effective ways to integrate existing resources into new and value added applications, that can also undergo run-time modifications, according to ever-changing execution conditions. Despite service-oriented architectural models are gaining momentum to tame the increasing complexity of composing and orchestrating distributed and heterogeneous functionalities, existing solutions generally lack a unified approach and only provide support for specific Ubiquitous Internet aspects. Moreover, they usually target rather static scenarios and scarcely support the dynamic nature of pervasive access to Internet resources, that can make existing compositions soon become obsolete or inadequate, hence in need of reconfiguration. This thesis proposes a novel middleware approach to comprehensively deal with Ubiquitous Internet facets and assist in establishing innovative application scenarios. We claim that a truly viable ubiquity support infrastructure must neatly decouple distributed resources to integrate and push any kind of content-related logic outside its core layers, by keeping only management and coordination responsibilities. Furthermore, we promote an innovative, open, and dynamic resource composition model that allows to easily describe and enforce complex scenario requirements, and to suitably react to changes in the execution conditions.

Architectures and design patterns for functional design of logic control and diagnostics in industrial automation

Recently in most of the industrial automation process an ever increasing degree of automation has been observed. This increasing is motivated by the higher requirement of systems with great performance in terms of quality of products/services generated, productivity, efficiency and low costs in the design, realization and maintenance. This trend in the growth of complex automation systems is rapidly spreading over automated manufacturing systems (AMS), where the integration of the mechanical and electronic technology, typical of the Mechatronics, is merging with other technologies such as Informatics and the communication networks. An AMS is a very complex system that can be thought constituted by a set of flexible working stations, one or more transportation systems. To understand how this machine are important in our society let considerate that every day most of us use bottles of water or soda, buy product in box like food or cigarets and so on. Another important consideration from its complexity derive from the fact that the the consortium of machine producers has estimated around 350 types of manufacturing machine. A large number of manufacturing machine industry are presented in Italy and notably packaging machine industry,in particular a great concentration of this kind of industry is located in Bologna area; for this reason the Bologna area is called “packaging valley”. Usually, the various parts of the AMS interact among them in a concurrent and asynchronous way, and coordinate the parts of the machine to obtain a desiderated overall behaviour is an hard task. Often, this is the case in large scale systems, organized in a modular and distributed manner. Even if the success of a modern AMS from a functional and behavioural point of view is still to attribute to the design choices operated in the definition of the mechanical structure and electrical electronic architecture, the system that governs the control of the plant is becoming crucial, because of the large number of duties associated to it. Apart from the activity inherent to the automation of themachine cycles, the supervisory system is called to perform other main functions such as: emulating the behaviour of traditional mechanical members thus allowing a drastic constructive simplification of the machine and a crucial functional flexibility; dynamically adapting the control strategies according to the different productive needs and to the different operational scenarios; obtaining a high quality of the final product through the verification of the correctness of the processing; addressing the operator devoted to themachine to promptly and carefully take the actions devoted to establish or restore the optimal operating conditions; managing in real time information on diagnostics, as a support of the maintenance operations of the machine. The kind of facilities that designers can directly find on themarket, in terms of software component libraries provides in fact an adequate support as regard the implementation of either top-level or bottom-level functionalities, typically pertaining to the domains of user-friendly HMIs, closed-loop regulation and motion control, fieldbus-based interconnection of remote smart devices. What is still lacking is a reference framework comprising a comprehensive set of highly reusable logic control components that, focussing on the cross-cutting functionalities characterizing the automation domain, may help the designers in the process of modelling and structuring their applications according to the specific needs. Historically, the design and verification process for complex automated industrial systems is performed in empirical way, without a clear distinction between functional and technological-implementation concepts and without a systematic method to organically deal with the complete system. Traditionally, in the field of analog and digital control design and verification through formal and simulation tools have been adopted since a long time ago, at least for multivariable and/or nonlinear controllers for complex time-driven dynamics as in the fields of vehicles, aircrafts, robots, electric drives and complex power electronics equipments. Moving to the field of logic control, typical for industrial manufacturing automation, the design and verification process is approached in a completely different way, usually very “unstructured”. No clear distinction between functions and implementations, between functional architectures and technological architectures and platforms is considered. Probably this difference is due to the different “dynamical framework”of logic control with respect to analog/digital control. As a matter of facts, in logic control discrete-events dynamics replace time-driven dynamics; hence most of the formal and mathematical tools of analog/digital control cannot be directly migrated to logic control to enlighten the distinction between functions and implementations. In addition, in the common view of application technicians, logic control design is strictly connected to the adopted implementation technology (relays in the past, software nowadays), leading again to a deep confusion among functional view and technological view. In Industrial automation software engineering, concepts as modularity, encapsulation, composability and reusability are strongly emphasized and profitably realized in the so-calledobject-oriented methodologies. Industrial automation is receiving lately this approach, as testified by some IEC standards IEC 611313, IEC 61499 which have been considered in commercial products only recently. On the other hand, in the scientific and technical literature many contributions have been already proposed to establish a suitable modelling framework for industrial automation. During last years it was possible to note a considerable growth in the exploitation of innovative concepts and technologies from ICT world in industrial automation systems. For what concerns the logic control design, Model Based Design (MBD) is being imported in industrial automation from software engineering field. Another key-point in industrial automated systems is the growth of requirements in terms of availability, reliability and safety for technological systems. In other words, the control system should not only deal with the nominal behaviour, but should also deal with other important duties, such as diagnosis and faults isolations, recovery and safety management. Indeed, together with high performance, in complex systems fault occurrences increase. This is a consequence of the fact that, as it typically occurs in reliable mechatronic systems, in complex systems such as AMS, together with reliable mechanical elements, an increasing number of electronic devices are also present, that are more vulnerable by their own nature. The diagnosis problem and the faults isolation in a generic dynamical system consists in the design of an elaboration unit that, appropriately processing the inputs and outputs of the dynamical system, is also capable of detecting incipient faults on the plant devices, reconfiguring the control system so as to guarantee satisfactory performance. The designer should be able to formally verify the product, certifying that, in its final implementation, it will perform itsrequired function guarantying the desired level of reliability and safety; the next step is that of preventing faults and eventually reconfiguring the control system so that faults are tolerated. On this topic an important improvement to formal verification of logic control, fault diagnosis and fault tolerant control results derive from Discrete Event Systems theory. The aimof this work is to define a design pattern and a control architecture to help the designer of control logic in industrial automated systems. The work starts with a brief discussion on main characteristics and description of industrial automated systems on Chapter 1. In Chapter 2 a survey on the state of the software engineering paradigm applied to industrial automation is discussed. Chapter 3 presentes a architecture for industrial automated systems based on the new concept of Generalized Actuator showing its benefits, while in Chapter 4 this architecture is refined using a novel entity, the Generalized Device in order to have a better reusability and modularity of the control logic. In Chapter 5 a new approach will be present based on Discrete Event Systems for the problemof software formal verification and an active fault tolerant control architecture using online diagnostic. Finally conclusive remarks and some ideas on new directions to explore are given. In Appendix A are briefly reported some concepts and results about Discrete Event Systems which should help the reader in understanding some crucial points in chapter 5; while in Appendix B an overview on the experimental testbed of the Laboratory of Automation of University of Bologna, is reported to validated the approach presented in chapter 3, chapter 4 and chapter 5. In Appendix C some components model used in chapter 5 for formal verification are reported.

A Design Methodology for Computer Security Testing

The field of "computer security" is often considered something in between Art and Science. This is partly due to the lack of widely agreed and standardized methodologies to evaluate the degree of the security of a system. This dissertation intends to contribute to this area by investigating the most common security testing strategies applied nowadays and by proposing an enhanced methodology that may be effectively applied to different threat scenarios with the same degree of effectiveness. Security testing methodologies are the first step towards standardized security evaluation processes and understanding of how the security threats evolve over time. This dissertation analyzes some of the most used identifying differences and commonalities, useful to compare them and assess their quality. The dissertation then proposes a new enhanced methodology built by keeping the best of every analyzed methodology. The designed methodology is tested over different systems with very effective results, which is the main evidence that it could really be applied in practical cases. Most of the dissertation discusses and proves how the presented testing methodology could be applied to such different systems and even to evade security measures by inverting goals and scopes. Real cases are often hard to find in methodology' documents, in contrary this dissertation wants to show real and practical cases offering technical details about how to apply it. Electronic voting systems are the first field test considered, and Pvote and Scantegrity are the two tested electronic voting systems. The usability and effectiveness of the designed methodology for electronic voting systems is proved thanks to this field cases analysis. Furthermore reputation and anti virus engines have also be analyzed with similar results. The dissertation concludes by presenting some general guidelines to build a coordination-based approach of electronic voting systems to improve the security without decreasing the system modularity.

Decomposition Methods and Network Design Problems

Decomposition based approaches are recalled from primal and dual point of view. The possibility of building partially disaggregated reduced master problems is investigated. This extends the idea of aggregated-versus-disaggregated formulation to a gradual choice of alternative level of aggregation. Partial aggregation is applied to the linear multicommodity minimum cost flow problem. The possibility of having only partially aggregated bundles opens a wide range of alternatives with different trade-offs between the number of iterations and the required computation for solving it. This trade-off is explored for several sets of instances and the results are compared with the ones obtained by directly solving the natural node-arc formulation. An iterative solution process to the route assignment problem is proposed, based on the well-known Frank Wolfe algorithm. In order to provide a first feasible solution to the Frank Wolfe algorithm, a linear multicommodity min-cost flow problem is solved to optimality by using the decomposition techniques mentioned above. Solutions of this problem are useful for network orientation and design, especially in relation with public transportation systems as the Personal Rapid Transit. A single-commodity robust network design problem is addressed. In this, an undirected graph with edge costs is given together with a discrete set of balance matrices, representing different supply/demand scenarios. The goal is to determine the minimum cost installation of capacities on the edges such that the flow exchange is feasible for every scenario. A set of new instances that are computationally hard for the natural flow formulation are solved by means of a new heuristic algorithm. Finally, an efficient decomposition-based heuristic approach for a large scale stochastic unit commitment problem is presented. The addressed real-world stochastic problem employs at its core a deterministic unit commitment planning model developed by the California Independent System Operator (ISO).

Safety by design: production of engineering surface modified nanomaterials

This PhD thesis focused on nanomaterial (NM) engineering for occupational health and safety, in the frame of the EU project “Safe Nano Worker Exposure Scenarios (SANOWORK)”. Following a safety by design approach, surface engineering (surface coating, purification process, colloidal force control, wet milling, film coating deposition and granulation) were proposed as risk remediation strategies (RRS) to decrease toxicity and emission potential of NMs within real processing lines. In the first case investigated, the PlasmaChem ZrO2 manufacturing, the colloidal force control applied to the washing of synthesis rector, allowed to reduce ZrO2 contamination in wastewater, performing an efficient recycling procedure of ZrO2 recovered. Furthermore, ZrO2 NM was investigated in the ceramic process owned by CNR-ISTEC and GEA-Niro; the spray drying and freeze drying techniques were employed decreasing NM emissivity, but maintaining a reactive surface in dried NM. Considering the handling operation of nanofibers (NFs) obtained through Elmarco electrospinning procedure, the film coating deposition was applied on polyamide non-woven to avoid free fiber release. For TiO2 NF the wet milling was applied to reduce and homogenize the aspect ratio, leading to a significant mitigation of fiber toxicity. In the Colorobbia spray coating line, Ag and TiO2 nanosols, employed to transfer respectively antibacterial or depolluting properties to different substrates, were investigated. Ag was subjected to surface coating and purification, decreasing NM toxicity. TiO2 was modified by surface coating, spray drying and blending with colloidal SiO2, improving its technological performance. In the extrusion of polymeric matrix charged with carbon nanotube (CNTs) owned by Leitat, the CNTs used as filler were granulated by spray drying and freeze spray drying techniques, allowing to reduce their exposure potential. Engineered NMs tested by biologists were further investigated in relevant biological conditions, to improve the knowledge of structure/toxicity mechanisms and obtain new insights for the design of safest NMs.

UWB radar sensor networks: Detection algorithms design and experimental analysis

In the last years radar sensor networks for localization and tracking in indoor environment have generated more and more interest, especially for anti-intrusion security systems. These networks often use Ultra Wide Band (UWB) technology, which consists in sending very short (few nanoseconds) impulse signals. This approach guarantees high resolution and accuracy and also other advantages such as low price, low power consumption and narrow-band interference (jamming) robustness. In this thesis the overall data processing (done in MATLAB environment) is discussed, starting from experimental measures from sensor devices, ending with the 2D visualization of targets movements over time and focusing mainly on detection and localization algorithms. Moreover, two different scenarios and both single and multiple target tracking are analyzed.

A navigation system for percutaneous needle interventions based on PET/CT images: design, workflow and error analysis of soft tissue and bone punctures

Percutaneous needle intervention based on PET/CT images is effective, but exposes the patient to unnecessary radiation due to the increased number of CT scans required. Computer assisted intervention can reduce the number of scans, but requires handling, matching and visualization of two different datasets. While one dataset is used for target definition according to metabolism, the other is used for instrument guidance according to anatomical structures. No navigation systems capable of handling such data and performing PET/CT image-based procedures while following clinically approved protocols for oncologic percutaneous interventions are available. The need for such systems is emphasized in scenarios where the target can be located in different types of tissue such as bone and soft tissue. These two tissues require different clinical protocols for puncturing and may therefore give rise to different problems during the navigated intervention. Studies comparing the performance of navigated needle interventions targeting lesions located in these two types of tissue are not often found in the literature. Hence, this paper presents an optical navigation system for percutaneous needle interventions based on PET/CT images. The system provides viewers for guiding the physician to the target with real-time visualization of PET/CT datasets, and is able to handle targets located in both bone and soft tissue. The navigation system and the required clinical workflow were designed taking into consideration clinical protocols and requirements, and the system is thus operable by a single person, even during transition to the sterile phase. Both the system and the workflow were evaluated in an initial set of experiments simulating 41 lesions (23 located in bone tissue and 18 in soft tissue) in swine cadavers. We also measured and decomposed the overall system error into distinct error sources, which allowed for the identification of particularities involved in the process as well as highlighting the differences between bone and soft tissue punctures. An overall average error of 4.23 mm and 3.07 mm for bone and soft tissue punctures, respectively, demonstrated the feasibility of using this system for such interventions. The proposed system workflow was shown to be effective in separating the preparation from the sterile phase, as well as in keeping the system manageable by a single operator. Among the distinct sources of error, the user error based on the system accuracy (defined as the distance from the planned target to the actual needle tip) appeared to be the most significant. Bone punctures showed higher user error, whereas soft tissue punctures showed higher tissue deformation error.

Robustness of speckle imaging techniques applied to horizontal imaging scenarios

Atmospheric turbulence near the ground severely limits the quality of imagery acquired over long horizontal paths. In defense, surveillance, and border security applications, there is interest in deploying man-portable, embedded systems incorporating image reconstruction methods to compensate turbulence effects. While many image reconstruction methods have been proposed, their suitability for use in man-portable embedded systems is uncertain. To be effective, these systems must operate over significant variations in turbulence conditions while subject to other variations due to operation by novice users. Systems that meet these requirements and are otherwise designed to be immune to the factors that cause variation in performance are considered robust. In addition robustness in design, the portable nature of these systems implies a preference for systems with a minimum level of computational complexity. Speckle imaging methods have recently been proposed as being well suited for use in man-portable horizontal imagers. In this work, the robustness of speckle imaging methods is established by identifying a subset of design parameters that provide immunity to the expected variations in operating conditions while minimizing the computation time necessary for image recovery. Design parameters are selected by parametric evaluation of system performance as factors external to the system are varied. The precise control necessary for such an evaluation is made possible using image sets of turbulence degraded imagery developed using a novel technique for simulating anisoplanatic image formation over long horizontal paths. System performance is statistically evaluated over multiple reconstruction using the Mean Squared Error (MSE) to evaluate reconstruction quality. In addition to more general design parameters, the relative performance the bispectrum and the Knox-Thompson phase recovery methods is also compared. As an outcome of this work it can be concluded that speckle-imaging techniques are robust to the variation in turbulence conditions and user controlled parameters expected when operating during the day over long horizontal paths. Speckle imaging systems that incorporate 15 or more image frames and 4 estimates of the object phase per reconstruction provide up to 45% reduction in MSE and 68% reduction in the deviation. In addition, Knox-Thompson phase recover method is shown to produce images in half the time required by the bispectrum. The quality of images reconstructed using Knox-Thompson and bispectrum methods are also found to be nearly identical. Finally, it is shown that certain blind image quality metrics can be used in place of the MSE to evaluate quality in field scenarios. Using blind metrics rather depending on user estimates allows for reconstruction quality that differs from the minimum MSE by as little as 1%, significantly reducing the deviation in performance due to user action.

DEVELOPMENT OF AN OPTIMIZATION MODEL FOR BIOFUEL FACILITY SIZE AND LOCATION AND A SIMULATION MODEL FOR DESIGN OF A BIOFUEL SUPPLY CHAIN

A range of societal issues have been caused by fossil fuel consumption in the transportation sector in the United States (U.S.), including health related air pollution, climate change, the dependence on imported oil, and other oil related national security concerns. Biofuels production from various lignocellulosic biomass types such as wood, forest residues, and agriculture residues have the potential to replace a substantial portion of the total fossil fuel consumption. This research focuses on locating biofuel facilities and designing the biofuel supply chain to minimize the overall cost. For this purpose an integrated methodology was proposed by combining the GIS technology with simulation and optimization modeling methods. The GIS based methodology was used as a precursor for selecting biofuel facility locations by employing a series of decision factors. The resulted candidate sites for biofuel production served as inputs for simulation and optimization modeling. As a precursor to simulation or optimization modeling, the GIS-based methodology was used to preselect potential biofuel facility locations for biofuel production from forest biomass. Candidate locations were selected based on a set of evaluation criteria, including: county boundaries, a railroad transportation network, a state/federal road transportation network, water body (rivers, lakes, etc.) dispersion, city and village dispersion, a population census, biomass production, and no co-location with co-fired power plants. The simulation and optimization models were built around key supply activities including biomass harvesting/forwarding, transportation and storage. The built onsite storage served for spring breakup period where road restrictions were in place and truck transportation on certain roads was limited. Both models were evaluated using multiple performance indicators, including cost (consisting of the delivered feedstock cost, and inventory holding cost), energy consumption, and GHG emissions. The impact of energy consumption and GHG emissions were expressed in monetary terms to keep consistent with cost. Compared with the optimization model, the simulation model represents a more dynamic look at a 20-year operation by considering the impacts associated with building inventory at the biorefinery to address the limited availability of biomass feedstock during the spring breakup period. The number of trucks required per day was estimated and the inventory level all year around was tracked. Through the exchange of information across different procedures (harvesting, transportation, and biomass feedstock processing procedures), a smooth flow of biomass from harvesting areas to a biofuel facility was implemented. The optimization model was developed to address issues related to locating multiple biofuel facilities simultaneously. The size of the potential biofuel facility is set up with an upper bound of 50 MGY and a lower bound of 30 MGY. The optimization model is a static, Mathematical Programming Language (MPL)-based application which allows for sensitivity analysis by changing inputs to evaluate different scenarios. It was found that annual biofuel demand and biomass availability impacts the optimal results of biofuel facility locations and sizes.

ARTHUR: A Collaborative Augmented Environment for Architectural Design and Urban Planning

Projects in the area of architectural design and urban planning typically engage several architects as well as experts from other professions. While the design and review meetings thus often involve a large number of cooperating participants, the actual design is still done by the individuals in the time in between those meetings using desktop PCs and CAD applications. A real collaborative approach to architectural design and urban planning is often limited to early paper-based sketches.In order to overcome these limitations, we designed and realized the ARTHUR system, an Augmented Reality (AR) enhanced round table to support complex design and planning decisions for architects. WhileAR has been applied to this area earlier, our approach does not try to replace the use of CAD systems but rather integrates them seamlessly into the collaborative AR environment. The approach is enhanced by intuitiveinteraction mechanisms that can be easily con-figured for different application scenarios.

Design of SOA services: experiences from industry

Because of the unknown usage scenarios, designing the elementary services of a service-oriented architecture (SOA), which form the basis for later composition, is rather difficult. Various design guide lines have been proposed by academia, tool vendors and consulting companies, but they differ in the rigor of validation and are often biased toward some technology. For that reason a multiple-case study was conducted in five large organizations that successfully introduced SOA in their daily business. The observed approaches are contrasted with the findings from a literature review to derive some recommendations for SOA service design.

Nonparametric location estimators in the randomized complete block design

Several tests for the comparison of different groups in the randomized complete block design exist. However, there is a lack of robust estimators for the location difference between one group and all the others on the original scale. The relative marginal effects are commonly used in this situation, but they are more difficult to interpret and use by less experienced people because of the different scale. In this paper two nonparametric estimators for the comparison of one group against the others in the randomized complete block design will be presented. Theoretical results such as asymptotic normality, consistency, translation invariance, scale preservation, unbiasedness, and median unbiasedness are derived. The finite sample behavior of these estimators is derived by simulations of different scenarios. In addition, possible confidence intervals with these estimators are discussed and their behavior derived also by simulations.

A simulation study of the standard design, the rolling six design, the CRM, and the modified CRM in Phase I clinical trials

The Phase I clinical trial is considered the "first in human" study in medical research to examine the toxicity of a new agent. It determines the maximum tolerable dose (MTD) of a new agent, i.e., the highest dose in which toxicity is still acceptable. Several phase I clinical trial designs have been proposed in the past 30 years. The well known standard method, so called the 3+3 design, is widely accepted by clinicians since it is the easiest to implement and it does not need a statistical calculation. Continual reassessment method (CRM), a design uses Bayesian method, has been rising in popularity in the last two decades. Several variants of the CRM design have also been suggested in numerous statistical literatures. Rolling six is a new method introduced in pediatric oncology in 2008, which claims to shorten the trial duration as compared to the 3+3 design. The goal of the present research was to simulate clinical trials and compare these phase I clinical trial designs. Patient population was created by discrete event simulation (DES) method. The characteristics of the patients were generated by several distributions with the parameters derived from a historical phase I clinical trial data review. Patients were then selected and enrolled in clinical trials, each of which uses the 3+3 design, the rolling six, or the CRM design. Five scenarios of dose-toxicity relationship were used to compare the performance of the phase I clinical trial designs. One thousand trials were simulated per phase I clinical trial design per dose-toxicity scenario. The results showed the rolling six design was not superior to the 3+3 design in terms of trial duration. The time to trial completion was comparable between the rolling six and the 3+3 design. However, they both shorten the duration as compared to the two CRM designs. Both CRMs were superior to the 3+3 design and the rolling six in accuracy of MTD estimation. The 3+3 design and rolling six tended to assign more patients to undesired lower dose levels. The toxicities were slightly greater in the CRMs.^