bluuebunny/crossref_metadata_2025 huggingface dataset:
Stormwater overflow impacts on the sanitary quality of bathing waters
Authors: Soyeux E. , Blanchet F. , Tisserand B.
Published: December 2007

New European Directive 2006/7/EC concerning the management of bathing water quality introduces the concept of ‘active management of bathing water sanitary quality’ which could lead to a temporary bathing prohibition in case of short term pollution. For the last three bathing seasons, Veolia has carried out in experimental mode this ‘active management’ concept at more than one hundred bathing sites with various characteristics. Results confirm the high level of microbiological pollution observed in sewer overflows during rainy periods, which is the main cause of bathing water quality deterioration. An on-line treatment solution has been successfully tested. This solution may be used in dense urban areas.
Escherichia coli in urban stormwater: explaining their variability
Authors: McCarthy D.T. , Mitchell V.G. , Deletic A. , Diaper C.
Published: December 2007

The development of a model that predicts the levels of microorganisms in urban stormwater will aid in the assessment of health risks when using stormwater for both recreational uses and as an alternate water resource. However, the development of such a model requires an understanding of the dominant processes that influence the behaviour of microorganisms in urban systems. Using simple and multiple regression analyses this paper determines the dominant processes which affect the inter-event variability of the microbial indicator Escherichia coli (E. coli ) in four urbanised catchments. The results reveal that a number of antecedent climatic conditions, together with rainfall intensity, can significantly explain the inter-event variation in wet weather E. coli levels.
Investigation of multimodal zeta potential and size distribution in chemical pulp process water
Authors: Leiviskä T. , Rämö J.
Published: December 2007

Multimodal zeta potential distribution in chemical birch pulp process water was studied by filtrating the water into fractions and subsequently measuring zeta potential, charge quantity, turbidity and organic substances. Filtrations were made using 12 μm, 1.6 μm, 1.2 μm, 0.45 μm and 0.1 μm membranes. The number of populations with different zeta potentials diminished with filtration. With the unfiltrated water, 12 μm and 1.6 μm filtrates, three or four different zeta potentials were observed. When the filtration was performed with a 1.2 μm membrane or smaller, only two populations of different zeta potentials were detected. The charge quantity steadily approached zero from unfiltrated water towards a 1.6 μm fraction filtrate. After that, it remained constant. Turbidity constantly decreased when using smaller membranes. The amount of wood extractives decreased to half with 0.1 μm filtration. No significant difference in the amount of carbohydrates and lignin between the filtrated fractions and the unfiltrated water was detected. A comparison dealing with particle size analysis between two different apparatuses was also made.
Occurrence of perfluoroalkyl sulfonates and carboxylates in German drinking water sources compared to other countries
Authors: Lange F.T. , Wenz M. , Schmidt C.K. , Brauch H.-J.
Published: December 2007

Different homologues of C4 to C8 perfluoroalkyl carboxylates (PFCAs) and perfluoroalkyl sulfonates (PFASs) were detected in German surface waters, bank filtrates, artificially recharged groundwaters, and drinking waters. If no point sources are located nearby, the typically measured levels are in the low ng/L range. In the presence of point sources, such as a fluorochemical production site, a leaching agricultural fertilizer contaminated with PFCAs and PFASs, or drained PFC containing fire-fighting foams, much higher concentrations in the μg/L range occur. This situation is similar in Germany and other countries.
Bromide removal by hydrotalcite-like compounds in a continuous system
Authors: Echigo S. , Itoh S. , Kuwahara M.
Published: December 2007

Bromide ion removal from a real water matrix by hydrortalcite-like compounds (HTCs) was attempted in a column reactor to control the formation of brominated disinfection by-products in drinking water treatment process. The performance of HTCs was found to be comparable to a commercially available ion exchange resin for relatively low alkalinity water. Also, it was deduced that HTCs are better than ion exchange resins for high sulfate water because of their unique ion selectivity. In addition, the ion exchange reactions by HTCs were faster than a commercially available resin. Thus, HTCs are expected to provide similar performance to organic resins without the concern about secondary contamination (i.e., elution of organic compounds from resins).
Thrombospondin-1 Is an Adipokine Associated With Obesity, Adipose Inflammation, and Insulin Resistance
Authors: Varma Vijayalakshmi , Yao-Borengasser Aiwei , Bodles Angela M. , Rasouli Neda , Phanavanh Bounleut , Nolen Greg T. , Kern Emily M. , Nagarajan Radhakrishnan , Spencer Horace J. , Lee Mi-Jeong , Fried Susan K. , McGehee Robert E. , Peterson Charlotte A. , Kern Philip A.
Published: December 2007

OBJECTIVE—We examined the relationship between the expression of thrombospondin (TSP)1, an antiangiogenic factor and regulator of transforming growth factor-β activity, obesity, adipose inflammation, and insulin resistance.

RESEARCH DESIGN AND METHODS—TSP1 gene expression was quantified in subcutaneous adipose tissue (SAT) of 86 nondiabetic subjects covering a wide range of BMI and insulin sensitivity, from visceral adipose (VAT) and SAT from 14 surgical patients and from 38 subjects with impaired glucose tolerance randomized to receive either pioglitazone or metformin for 10 weeks. An adipocyte culture system was also used to assess the effects of pioglitazone and coculture with macrophages on TSP1 gene expression.

RESULTS—TSP1 mRNA was significantly associated with obesity (BMI) and insulin resistance (low insulin sensitivity index). Relatively strong positive associations were seen with markers of inflammation, including CD68, macrophage chemoattractant protein-1, and plasminogen activator inhibitor (PAI)-1 mRNA (r ≥ 0.46, P = 0.001 for each), that remained significant after controlling for BMI and Si. However, TSP1 mRNA was preferentially expressed in adipocyte fraction, whereas inflammatory markers predominated in stromal vascular fraction. Coculture of adipocytes and macrophages augmented TSP1 gene expression and secretion from both cell types. Pioglitazone (not metformin) treatment resulted in a 54% decrease (P < 0.04) in adipose TSP gene expression, as did in vitro pioglitazone treatment of adipocytes.

CONCLUSIONS—TSP1 is a true adipokine that is highly expressed in obese, insulin-resistant subjects; is highly correlated with adipose inflammation; and is decreased by pioglitazone. TSP1 is an important link between adipocytes and macrophage-driven adipose tissue inflammation and may mediate the elevation of PAI-1 that promotes a prothrombotic state.
Moisture Sensitivity of Modified Asphalt Binders
Authors: Copeland Audrey R. , Youtcheff Jack , Shenoy Aroon
Published: December 2007

Bond strength is a critical parameter in evaluating a binder's ability to resist moisture-induced damage. The influence of polymer modification, moisture conditioning, and long-term aging on the bond strength of asphalt binders was measured by means of the modified pull-off test method previously developed to evaluate moisture sensitivity of asphalt binders using the pneumatic adhesion tensile testing instrument (PATTI). The pull-off test is able to distinguish between binders with the same performance grade but different chemical properties due to modification. However, the exact effect of modification on bond strength cannot be determined without consideration of the binder's physical properties. Moisture conditioning was the most influential factor on bond strength. Long-term laboratory aging increased cohesive strength of asphalt binders. However, aging combined with moisture conditioning decreased adhesive strength of binders. Comparisons of binder resistance to permanent deformation with pull-off tensile strength highlight the need for a test method that measures adhesive properties, namely, bond strength, of asphalt binder and mastics. Finally, recommendations are provided to improve the ability of the pull-off test method to determine bond strength.
Impact of Lime and Liquid Antistrip Agents on Properties of Idaho Hot-Mix Asphalt Mixture
Authors: Sebaaly Peter E. , Little Dallas , Hajj Elie Y. , Bhasin Amit
Published: December 2007

In 2005, the Idaho Transportation Department constructed a field project on State Highway 67 (SH-67) to evaluate the impact of hydrated lime and a liquid antistrip agent on the mechanical properties of an Idaho hot-mix asphalt (HMA) mixture. This paper documents the results of a laboratory evaluation on field-produced HMA mixtures sampled from lime and liquid antistrip test sections on SH-67. As the two mixtures were subjected to multiple freeze-thaw (F-T) cycles, the mixture treated with hydrated lime (lime mixture) maintained good resilient-modulus properties over the entire 21 F-T cycles. The mixture treated with the liquid antistrip agent (liquid mixture) fully disintegrated after 22 F-T cycles. The results of a mechanistic analysis showed that, as a result of multiple F-T cycling, the liquid mixture will incur a 220% increase in potential rutting compared with the lime mixture, which will incur only a 65% potential increase in rutting. The dynamic moduli in compression demonstrated that both dry and moisture-conditioned lime mixtures can be considered less susceptible to rutting compared with liquid mixtures. Furthermore, the lime mixtures demonstrated better resistance to moisture damage than the liquid mixtures on the basis of the ratio of dynamic modulus in tension of moisture-conditioned to dry mixtures. The additional stiffness of the lime mixtures did not contribute to premature fatigue cracking when mixtures were subjected to dynamic creep testing in the tensile mode of loading.
Autonomous Detection and Anticipation of Jam Fronts from Messages Propagated by Intervehicle Communication
Authors: Schönhof Martin , Treiber Martin , Kesting Arne , Helbing Dirk
Published: December 2007

A minimalist, completely distributed freeway traffic information system is introduced. It involves autonomous, vehicle-based jam-front detection, information transmission via intervehicle communication, and forecast of the spatial position of jam fronts by reconstructing the spatiotemporal traffic situation on the basis of the transmitted information. The whole system is simulated with an integrated traffic simulator, which is based on a realistic microscopic traffic model for longitudinal movements and lane changes. The function of its communication module has been explicitly validated by comparing the simulation results with analytical calculations. By means of simulations, it is shown that the algorithms for congestion-front recognition, message transmission, and processing reliably predict the existence and position of jam fronts for vehicle equipment rates as low as 3%. A reliable mode of operation for small market penetrations is crucial for successful introduction of intervehicle communication. The short-term prediction of jam fronts is not only useful for the driver but also essential for enhancing road safety and road capacity by intelligent adaptive cruise control systems.
General Lane-Changing Model MOBIL for Car-Following Models
Authors: Kesting Arne , Treiber Martin , Helbing Dirk
Published: December 2007

A general model (minimizing overall braking induced by lane change, MOBIL) is proposed to derive lane-changing rules for discretionary and mandatory lane changes for a wide class of car-following models. Both the utility of a given lane and the risk associated with lane changes are determined in terms of longitudinal accelerations calculated with microscopic traffic models. This determination allows for the formulation of compact and general safety and incentive criteria for both symmetric and asymmetric passing rules. Moreover, anticipative elements and the crucial influence of velocity differences of these car-following models are automatically transferred to the lane-changing rules. Although the safety criterion prevents critical lane changes and collisions, the incentive criterion takes into account the advantages and disadvantages of other drivers associated with a lane change via the “politeness factor.” The parameter allows one to vary the motivation for lane changing from purely egoistic to more cooperative driving behavior. This novel feature allows one first to prevent lane changes for a marginal advantage if they obstruct other drivers and second to let an aggressive driver induce the lane change of a slower driver ahead in order to no longer be obstructed. This phenomenon is common for asymmetric passing rules with a dedicated lane for passing. The model is applied to traffic simulations of cars and trucks with the intelligent driver model as the underlying car-following model. An open system with an on-ramp is studied, and the resulting lane-changing rate is investigated as a function of the spatial coordinate as well as a function of traffic density.
Driver Heterogeneity in Car following and Its Impact on Modeling Traffic Dynamics
Authors: Ossen Saskia , Hoogendoorn Serge P.
Published: December 2007

A dedicated trajectory data collection method using a helicopter enabled a range of in-depth empirical studies of car-following behavior. These studies found a high degree of heterogeneity in car-following behavior; that is, drivers' driving styles turned out to be highly different because different modeling approaches were needed to model these behaviors satisfactorily. Therefore the impact of heterogeneity in car following on modeling traffic dynamics is examined to gain insight into the effect of incorporating different types and degrees of heterogeneity in car-following behavior on the dynamics of a simulated traffic flow. The microsimulation approach that was adopted focused on two case studies: the first case study focused on heterogeneity in parameter values by comparing stability results for heterogeneous platoons and homogeneous platoons, which could in fact be seen as a solid preparation for the second case study. The second study was a simulation of a fixed stretch of road on which, from a certain point on, a speed limit was imposed for the drivers. In this case study the link between the empirical results and the simulations was strengthened as several types of heterogeneity (e.g., different model specifications for different drivers and different parameter settings and combinations of them) were explored and compared with the empirically estimated parameters. Both analyses show clear differences between simulations with homogeneous drivers and simulations with heterogeneous drivers.
Steady-State Solutions and Multiclass Calibration of Gipps Microscopic Traffic Flow Model
Authors: Punzo Vincenzo , Tripodi Antonino
Published: December 2007

This study addresses the problem of calibration of the Gipps microscopic traffic flow model. The approach consists of first deriving traffic stream models, in the form of steady-state solutions of car-following models, and then fitting such models to stationary traffic data. To this end, traffic stream models for the Gipps model were first attained, and an explicit formula for the flow at capacity as a function of microscopic parameters is provided. Analysis of the models for different combinations of microscopic parameters explains the widely held belief that the Gipps model is unable to reproduce unstable traffic phenomena. To be suitable for model parameter calibration in simulation practice, single-class models were generalized to a multiclass traffic scenario for which a calibration procedure was developed. Once applied to real motorway traffic data, the multiclass scenario proved its effectiveness in terms of error statistics. Values of calibrated parameters were all significant and consistent with expectations. Moreover, they were consistent with the observed aggregate measures (e.g., flow at capacity). Finally, unlike nonstationary, model-based approaches, the computing time required by the multiclass calibration presented is negligible, allowing calibration of a large number of parameters, that is, calibration of different classes of vehicles.
Examining Headway Distribution Models with Urban Freeway Loop Event Data
Authors: Zhang Guohui , Wang Yinhai , Wei Heng , Chen Yanyan
Published: December 2007

Vehicle headway distribution is fundamental for several important traffic research and simulation issues. Many headway models have been developed over the past decades. Each has its own strength and weakness. Selection of the most suitable model for a certain traffic condition remains an open issue. A comprehensive study of the performance of typical headway distribution models on urban freeways is presented. With the advanced loop event data analyzer system, many accurate headway observations were obtained from I-5 in the area of Seattle, Washington. These headway data were used to calibrate and examine the performance of various headway models. The goodness of fit for several most commonly used headway distribution models was investigated by using headways observed on regular lanes and high-occupancy-vehicle (HOV) lanes from different time periods of day. To evaluate the performance of these headway models, the analytical Kolmogorov-Smirnov test statistic and visualized comparison curves were used to measure and reflect their overall goodness of fit to the collected headway data. Although each model has its own practicability to a certain extent, the test results showed that the double-displaced negative exponential distribution model provided the best fit to these urban freeway headway data, especially for HOV lanes at wideranging flow levels. The shifted lognormal distribution also fits the general purpose lane headways very well. As a byproduct, a new standard parameter estimation method was developed for calibrating complex multiparameter headway models.
Comparison of Quality of Service in Two Central Business Districts
Authors: Vo Phong Thanh , Mattingly Stephen P. , Ardekani Siamak , Dilshad Yasmin
Published: December 2007

In 2003-2004, the City of Fort Worth, Texas, undertook an exercise to retime traffic signals, to convert several one-way streets to two-way streets, and to make significant changes to the land use in the downtown area. Those changes were expected to have a significant impact on the quality of service of the downtown street network. After an urban street network undergoes modifications of its control system or geometric configuration as in Fort Worth, there is a need to have quantifiable tools to perform before-and-after studies on network quality of service. The purpose of this study was to use the two-fluid model to compare network performance over time and after a recent major modification. In 1983 and 1994, the two-fluid model was calibrated for the Dallas and Arlington, Texas, networks. The model was then recalibrated for the two networks with data collected in 2003; this allowed comparisons of the quality of traffic service in these networks over a long time. To assess the changes in Fort Worth, a new model was calibrated with data collected in 2004 and was then compared with the previous model calibrated in 1999. This comparison helped determine the success of signal retiming strategies as well as modifications in street geometry and land use. As expected, changes occurred in the system over time, but those changes, both positive and negative, differed, depending on the city.
Wisconsin Passenger and Freight Statewide Model
Authors: Proussaloglou Kimon , Popuri Yasasvi , Tempesta Daniel , Kasturirangan Krishnan , Cipra David
Published: December 2007

This paper reports the model validation process for a passenger and a freight statewide model developed for the Wisconsin Department of Transportation. These policy-sensitive planning models are used to understand and quantify passenger and freight flows in Wisconsin and to support system-planning analyses at a statewide level. Examples of policies being tested include the impact of different land use scenarios and transportation projects on highway traffic, the diversion of traffic along key corridors, and the ridership potential of enhanced intercity bus service. The passenger model was estimated by using the Wisconsin add-on for the 2001 National Household Travel Survey (NHTS), and the freight model was estimated by using Transearch commodity flow data. Model validation relied on the NHTS data, statewide automobile and truck traffic counts, intercity transit ridership estimates, and 2000 U.S. Census data including the Census Transportation Planning Package, FHWA's validation manual, and NCHRP Report 365. The Wisconsin statewide models are presented as case studies to highlight the data sources, model estimation and validation methodologies, and results obtained at a statewide level. The passenger and freight validation results support the robustness of the models at a statewide and a corridor level. The methodology and standards discussed for the Wisconsin statewide models provide another data point to help establish guidelines for statewide model validation.
Algebraic Geometry
Authors: Cox David A.
Published: December 2007

Algebraic geometry is an area of mathematics that concerns the interaction between algebra and goemetry. This article discusses some main algebraic and geometric objects of interest in algebraic geometry. Computational methods and abstract theories are discussed, and some main applications to computer science are indicated.
Fractals
Authors: Mendivil F.
Published: December 2007

We introduce a fractal as a mathematical object that has strong scaling behavior. That is, its “behavior” at one scale is strongly related to its “behavior” at finer scales. We give examples of many different types of geometric fractals and then introduce other types of fractal objects, like fractal functions or fractal random processes. These fractals can have exact scaling, approximate scaling, or only statistical scaling behavior. A particularly nice class of fractals are those defined by the iterated function system (IFS). We give an application of IFS fractals to image representation and close with some brief comments on a relationship between fractals and wavelets.
Linear and Nonlinear Programming
Authors: Solow Daniel
Published: December 2007

Linear programs (LPs) and nonlinear programs (NLPs) are mathematical problems in which data are used to find the values of variables that minimize or maximize an objective function while simultaneously satisfying several imposed constraints on the values of the variables. Such problems arise frequently in computer science, mathematics, business, economics, statistics, engineering, operations research, and the sciences. An overview of the similarities and differences between LPs and NLPs is presented here. For example, although the art of building LP and NLP models involves identifying the variables, objective function, and constraints, methods for solving such problems differ greatly. A finite procedure has been developed to solve all LPs; however, no such procedure is available for solving NLPs.
Pattern Recognition
Authors: Schalkoff Robert J.
Published: December 2007

Pattern recognition (PR) concerns the description or classification (recognition) of measurements. PR capability is often a prerequisite for intelligent behavior. PR is not one technique, but rather a broad body of often loosely related knowledge and techniques. PR may be characterized as an information reduction, information mapping, or information labeling process. Historically, the two major approaches to pattern recognition are statistical (or decision theoretic), hereafter denoted StatPR, and syntactic (or structural), hereafter denoted SyntPR. The technology of artificial neural networks has provided another alternative, neural pattern recognition, hereafter denoted NeurPR. NeurPR is especially well suited for “black box” implementation of PR algorithms. As no single technology is always the optimal solution for a given PR problem, all three are often considered in the quest for a solution.
Probability and Statistics
Authors: Johnson James
Published: December 2007

After a brief historical account of probability's evolution over the past five centuries, the article presents techinical overviews of concepts that are central to computer science and engineering applications. These areas are probability spaces, combinatorics, random variables and their distributions, convergence modes, computer simulations, and statistical inference. Each section begins with elementary definitions, continues with the most frequently used techniques and theorems, and concludes with more advanced results. Examples and typical computations accompany the presentations.
Shared Memory Multiprocessors
Authors: Zhang Li , Parashar Manish
Published: December 2007

Shared memory multiprocessors are multiprocessor systems that logically implement a single global address space. The model for parallel programming based on such systems, the shared address space model, is straightforward and frees programmers from the tedious and sometimes complicated task of orchestrating all communication and snychronization through explicit message passing to access remote data. As a result, this class of multiprocessor systems has received much commercial as well as research interest.
Software Product Certification
Authors: Voas Jeffrey
Published: December 2007

Here, we examine the process and challenges of certifying software‐intensive systems. We will first review the interpretation of the term,
certification
. We then review different types of certification processes, and discuss challenges to forming software certification procedures. And finally, we discuss a strategy for gaining the maximum benefit from performing certification by formulating the correct procedures that are needed to roll out a certification plan by recommending appropriate guidelines to those developers whose products will be judged.
Data Privacy
Authors: Beresford Alastair , Scott David
Published: December 2007

Data arepersonally identifiableif they can be attributed to a particular individual. Therefore,data privacyis concerned with the protection of personally identifiable information that, if unconditionally published, would violate an individual's privacy. For example, the right to solitude is violated if surveillance cameras peer into homes and are used to monitor the activities of occupants. An individual's right to secrecy is broken if personal health or financial data are made public. The right to anonymity is jeopardized by a system requiring all shop customers to provide identity documents when making purchases.
Graph Theory and Algorithms
Authors: Kagaris Dimitri , Tragoudas Spyros
Published: December 2007

Overview of graph theory: graphs, complexity of algorithms, and graph problem formulations and solutions.
Behavioral Sciences and Computing
Authors: Barnhart Steven M. , Lisi Richard De
Published: December 2007

This article presents an overview of behavioral science research on human–computer interactions. The research is peresented according to the following three categories: (1) antecedent‐consequence effects, (2) model building, and (3) individual‐social perspectives. The first category, antecedent‐consequent effects, asks questions such as follows: How does variability in human abilities, traits, and prior performance affect computer use? How does use of computers affect variability in human abilities, traits, and subsequent performance? The second category, model building, consists of research on the nature of human abilities and performance using metaphors form computer science and related fields. Here, the behavioral scientist is primarily interested in understanding the nature of human beings but uses computer metaphors as a basis for describing and explaining human behavior. Model building can also start with assumptions about the nature of human beings, for example, limitations of human attention or types of motivation that serve as the basis for the development of new products and applications for human use. The third category, individual‐social perspective, investigates the effects of increased access to and acceptance of computers in everyday life on human social relations. Questions addressed here are those such as follows: Do computers serve to isolate or connect persons to one another? What are the implications of lack of either access or acceptance of computers in modern cultures? Given the sheer quantity of empirical invesigations in behavioral sciences computing research, the reader should appreciate the highly selective nature of this article.
Non‐Inferiority Trial
Authors: Hung H. M. James , Wang Sue‐Jane , O'Neill Robert
Published: December 2007

Noninferiority trials employ a selected active‐control treatment, the effect of which has been established in historical placebo‐controlled trials. The active control serves as a comparator for evaluating the effect of an experimental treatment. A placebo arm may be either present in or absent from the noninferiority trial, depending on whether use of the placebo arm is feasible. In contrast with showing superiority, it is much more challenging to design a “show noninferiority” trial. The notion of noninferiority is extremely difficult to define, and a threshold termed “noninferiority margin” must be determined to define the noninferiority hypothesis for testing. The margin determination depends on many key factors: the objective of the noninferiority trial, critical assumptions pertaining to the ability of a trial to distinguish between an effective and an ineffective treatments, and the applicability of the historical estimate of the active control's effect to the noninferiority trial when the placebo cannot be used, and so forth. This article is intended to pinpoint the factors critically needing consideration for the viability of using a noninferiority trial to evaluate the effect of an experimental treatment.
Multistage Genetic Association Studies
Authors: Thomas Duncan , Conti David
Published: December 2007

The practice of individualized medicine for therapy or prevention could be informed by studies of genetic modifiers of treatment effects. This special case of gene–environment interaction studies offers several unique opportunities by exploiting random assignment of treatments. Two basic approaches are possible, one based on genetic studies added to a preexisting randomized controlled trial, the other based on targeted intervention studies added to a preexisting genetic cohort study. We focus in particular on multistage sampling designs that exploit the prior information from the parent study to improve the statistical efficiency of the study of genetic modifiers of treatment effects. In particular, we discuss different contexts in which either design might be used—a study of a single candidate gene, an entire pathway, or a genome‐wide association scan.
Minimum Effective Dose (MinED)
Authors: Thomas Neal , Ting Naitee
Published: December 2007

The minimum effective dose (MinED or MED) defines a lower bound for therapeutically useful doses. The MinED is important because most drugs have increasing potential for safety problems as dose is increased. The MinED is typically studied during phase II of drug development. A concise definition of the MinED from the International Conference on Harmonization (ICH) guidelines is “the smallest dose with a discernible useful effect.” We discuss methods to give operational meaning to the descriptors “useful” and “discernible.”
Cooperative North Scandinavian Enalapril Survival Study (
CONSENSUS
)
Authors: Snapinn Steven M.
Published: December 2007

The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) was a landmark trial that demonstrated a large and highly significant reduction in mortality with the angiotensin‐converting enzyme inhibitor, enalapril, in patients with severe heart failure. Although the study was designed to enroll 400 patients, CONSENSUS terminated with only 253 patients due to a recommendation from the ethics review committee. The overall mortality rates were 68 of 126 placebo patients (54%) and 50 of 127 enalapril patients (39%);
P
 = 0.003. Additional analyses suggested that the effect of enalapril on mortality is related to hormonal activation, particularly to activation of the renin‐angiotensin system. Surviving CONSENSUS patients were followed for an additional 10 years after termination of the trial, at which time five patients remained alive, all from the enalapril group.
Therapeutic Index
Authors: Abughazaleh Raed D. , Tracy Timothy S.
Published: December 2007

Therapeutic index is an expression of the relative toxicity as compared to efficacy of a given compound. In animal studies, it can be computed as the ratio of the median lethal dose (LD50) to the median effective dose (ED50). In humans, it is frequently expressed as the ratio of the median toxic dose (TD50) to the ED50. Several issues limit the utility of the therapeutic index, and to‐date there remains no official list of drugs considered to possess narrow therapeutic indices. Mortality is a poor measure of a drug's toxicity and raises ethical concerns in animal studies. Similarly, ED50can be a poor measure of a drug's effectiveness because of lack of consistency in endpoint biomarkers and because the ED50may be different for multiple conditions the drug may be used to treat. When LD50and ED50are obtained in animals, any extrapolation to humans is limited. In addition, multiple factors of interindividual and intraindividual variability exist in humans and can limit the utility of a therapeutic index estimate. Interindividual variability can be caused by either pharmacokinetic or pharmacodynamic differences, and may play an important role in brand‐to‐generic switching of narrow therapeutic index drugs. Intraindividual variability can also be related to physiologic factors that affect absorption, distribution, metabolism, or excretion of a drug. In conclusion, use of a therapeutic index requires an understanding of its limitations, and may be most useful in the preclinical stages of drug testing where limited experience of the drug's administration is available. To date, there remains no official guidance to research laboratories and pharmaceutical companies on the optimal use of therapeutic index.
Optimal Biological Dose for Molecularly‐Targeted Therapies
Authors: Ahn Chul , Kang Seung‐Ho , Xie Yang
Published: December 2007

Phase I cancer clinical trials are small dose‐finding studies designed to rapidly identify the optimal dose of a new anticancer agent. The optimal dose has been defined as the maximum tolerated dose (MTD) for conventional cytotoxic anticancer drugs, and this dose is typically recommended as the phase II dose. In the past decade, a new approach for cancer treatment has emerged. This new approach, now widely referred to as “molecularly targeted therapy” is designed a priori, based on the knowledge of various physiological molecules that have been obtained by the development of molecular biology. Most molecularly targeted agents slow or stop the growth of tumors. Such agents are, in general, less toxic than conventional cytotoxic agents; as a result, the maximum therapeutic effect may occur at doses well below the MTD. With the emergence of a growing number of molecularly targeted agents, approaches to early drug development are changing. We present dose‐finding designs for phase I clinical trials of molecularly targeted drugs. There is an increasing need to develop designs to find the optimal biological dose for molecularly targeted agents, and the utility of designs needs to be prospectively evaluated in future clinical dose‐finding trials for a variety of molecularly targeted agents.
PhaseIIITrials
Authors: Mallinckrodt Craig , Whitmyer Virgil
Published: December 2007

The objective of phase III clinical trials is to confirm the preliminary but inconclusive evidence obtained from phase II studies that a drug is safe and effective for the intended indication in the relevant patient population. Phase III studies provide the primary basis upon which drugs are approved for use by the various regulatory agencies. Because no universally best approach to phase III research exists, it is important to tailor features of the study to the specific situation at hand. This article focuses on the key aspects of the design, conduct, and analysis of phase III trials and the trade‐offs between them that are necessary to consider when designing a trial intended to yield confirmatory evidence of a drug's effect. Nevertheless, even the best designed trials will have limitations. Any one trial may address its primary hypotheses with little or no ambiguity while other important questions remain unresolved. Therefore, information from the current trial, coupled with knowledge from earlier trials, is used to continually reevaluate what is known. With this knowledge one must reconsider what important questions remain unresolved, and continue to plan and conduct appropriate studies to address the unresolved questions.
Prognostic Variables in Clinical Trials
Authors: Berger Vance W. , Sankoh A. J.
Published: December 2007

Identifying and making appropriate use of influential prognostic factors in the design and analysis of clinical trials is important. The discussion focuses on the nature and validity of covariates, and some statistical considerations for the selection of and adjustment for important prognostic factors.
Simple Randomization
Authors: Perevozskaya Inna T.
Published: December 2007

An overview of general concept of randomization is given, and its importance as a crucial part of the study design to avoid selection bias is stressed. Simple randomization is the first and most intuitive of the randomization methods. Other, more sophisticated, methods of randomization are highlighted. We discuss properties of the simple randomization and its relationship to other randomization methods. Concept and properties of stratified randomization are discussed as well.
Enrichment Design
Authors: Fedorov Valerii V. , Liu Tao
Published: December 2007

Enrichment designs usually consist of two or three stages, where the first stage serves as a screening process for selecting a certain subpopulation, and the succeeding stages serve to distinguish the treatment effect from the placebo effect, within the selected (enriched) subpopulation. The efficiency of its efficacy (response) detection comes at the expense of the ability to make inferences for the general population; that is, the results are valid only for the selected subpopulation. At the same time, if a valid partitioning of the population is proven, then it might be viewed as evidence of “latent” classifiers, which can be targeted for a search. Statistical analysis commonly makes explicit use of the outcomes from only the selected subpopulation (final stage). Some simple models can take advantage of the outcomes from all stages. Most published studies using these designs have been conducted in the field of clinical oncology, but enrichment designs have become increasingly popular in various therapeutic areas.
Therapeutic Equivalence
Authors: Wiens Brian L.
Published: December 2007

We consider studies of therapeutic equivalence. Such studies aim to show that two treatments have similar efficacy. The context is of high importance, and situations in which therapeutic equivalence trials are appropriate are discussed. Choosing an equivalence limit is important to rule out the possibility that a placebo can be considered equivalent to a treatment with benefit. The two one‐sided tests approach is common and uses a Neyman‐Pearson framework for hypothesis testing although the test is commonly conducted by comparing the bounds of a confidence interval to the equivalence limit. Study conduct will be subjected to high scrutiny because poor study conduct can result in the perception of an increased chance of demonstrating equivalence. Some other aspects of a therapeutic equivalence trial are also discussed, including power and choice of an analysis set.
Ministry of Health, Labour and Welfare (
MHLW
, Japan)
Authors: Ono Shunsuke
Published: December 2007

The regulation of clinical trials and new drug approval in Japan is based on the Pharmaceutical Affairs Law (PAL) and related ordinances. The Ministry of Health, Labour and Welfare (MHLW) is the governmental body responsible for enacting legislation for pharmaceutical affairs. The MHLW makes final decisions on whether it should halt trials for which investigational new drugs notifications (INDs) are submitted, and whether it should approve drugs for which New Drug Applications (NDAs) are submitted. The Pharmaceuticals and Medical Devices Agency (PMDA) is a semi‐governmental agency established by law that conducts scientific review of INDs and NDAs via internal review teams. The role of the PMDA as a review agency has become critical in pharmaceutical research and development activities, with recent progress in global regulatory harmonization and the necessity for cooperation between the regulator and the industry. The The PMDA also provides consultation services for clinical development, similar to those by the U.S. Food and Drug Administration. Historically, Japanese regulations have evolved by gradually accepting Western regulatory components into preexisting ones. Although most basic regulatory structures are similar to those in Western countries, there are still some obvious differences, including the applicability of INDs. Facing the recent decline in the numbers of domestic trials, the MHLW has issued several measures to promote domestic trials, including grants to train hospital staffs, but it is not expected that the decline will reverse easily because it is related to a diminishing demand for Japanese trials in response to the globalization of pharmaceutical research and development.
Equivalence Trials and Equivalence Limits
Authors: Hung H. M. James
Published: December 2007

An equivalence trial employs a selected active control treatment as a comparator for evaluating the effect of a test treatment. The notion of equivalence is that the difference between the test treatment and the active control is clinically insignificant with respect to therapeutic benefits or an adverse effect at issue. The threshold of clinical insignificance or indifference must be defined and is often termed “equivalence margin” or “equivalence limit.” In clinical trials, the study question that is more often of primary interest is the noninferiority hypothesis that the test treatment is clinically acceptably inferior to the control. Determination of the noninferiority hypothesis with a specified margin often requires special considerations pertaining to other study objectives, such as showing that the test treatment retains a certain fraction of the control's effect. These special considerations in defining a noninferiority margin may not be applicable to defining the superiority margin in the equivalence hypothesis.
Phase
I
/
II
Clinical Trials
Authors: Zohar Sarah
Published: December 2007

The objective of dose‐finding phase I/II studies is to find an optimal dose level that corresponds to some given acceptable toxicity rate combined with a minimal response rate of a new drug or procedure. Most published phase I/II trials have been designed to determine the maximum tolerated dose during a phase I trial and subsequently to determine the response rate during a phase II trial. Recently, there has been increasing research in the development of dose‐finding methodologies, based on joint modeling of toxicity and efficacy outcomes in the same protocol that aim at minimizing the sample size in case of unacceptable high toxicity or unacceptable low efficacy. The available dose‐finding designs for phase I/II trials are presented with specific regard for new designs that jointly model toxicity and efficacy outcome.
Preference Trials
Authors: Campbell Marion K. , Torgerson David J.
Published: December 2007

Although the randomized controlled trial is widely accepted as the design of choice for evaluating health‐care interventions, it requires that all participants are prepared to accept allocation to any of the interventions under study. When patients have a strong preference to receive one of the study interventions, this can lead to difficulties with compliance and potentially to biased assessment of outcomes. The patient preference trial has been proposed as a potential solution, with patients with strong preferences being allocated to their treatment of choice and those with no strong preference being randomized in the standard manner. All patients are followed up and outcomes assessed. We discuss the effects of patient preference and review the advantages and disadvantages of the patient preference design.
PhaseIITrials
Authors: Keene Oliver N.
Published: December 2007

Phase II trials have two aims:(1)to provide a proof of concept that the drug is able to affect the disease it is designed to affect without overt safety problems and(2)to define the dose(s) to be taken forward to phase III. Trials that specifically address these issues are often referred to as phase IIa and phase IIb trials, respectively. Therefore, phase II trials provide the initial test of efficacy and reassurance on safety in patients and, if successful, define the dose or doses to be carried forward to be studied in the wider populations and longer‐term phase III trials.
Absolute Risk Reduction
Authors: Newcombe Robert G.
Published: December 2007

This article considers confidence interval methods for differences between proportions. In line with well‐known corresponding results for the single proportion, the simplest Wald confidence intervals perform poorly. Several better methods are described, and illustrated using data from two small clinical trials. Selected methods are readily implemented using Excel resources freely downloadable from the author's website.
Effects of meteorology, astronomical variables, location and human disturbance on the singing apes: Hylobates albibarbis
Authors: Cheyne Susan M.
Published: December 2007

Gibbons are characterized by their species‐specific calls. The frequency of singing is known to be affected by rainfall, with singing occurring less in the wet season. I investigate the hypothesis that gibbon singing is also affected by the natural light‐dark cycle, and by the changing light intensity and air quality resulting from the smoke haze which blankets the Indonesian island of Borneo on a yearly basis. I compare three singing variables—onset of singing, average duration of singing bout and number of female great calls produced during the dry season of 2006 when there was no smoke haze (June–August) and when there was smoke haze present (September–November). I present evidence which indicates that the changes in singing behavior are affected by changes in rainfall and smoke intensity but not by other meteorological factors (i.e. wind and light intensity) or changing astronomical cues (light intensity, month, time of sunrise, time of moonrise, nocturnal illumination index, day length and night length). The possible long‐term effects of this on gibbon behavior and territoriality are discussed. The need to carry out more research on the long‐term effects of the smoke haze on wildlife behavior and possible solutions to the problem are discussed. Am. J. Primatol. 70:386–392, 2008. © 2007 Wiley‐Liss, Inc.