bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the Relationship Between the Content of Online Word of Mouth, Advertising, and Brand Performance
Authors: Gopinath Shyam , Thomas Jacquelyn S. , Krishnamurthi Lakshman
Published: January 2014

We study the relative importance of online word of mouth and advertising on firm performance over time since product introduction. The current research separates the volume of consumer-generated online word of mouth (OWOM) from its valence, which has three dimensions—attribute, emotion, and recommendation oriented. Firm-initiated advertising content is also classified as attribute or emotion advertising. We also shed light on the role played by advertising content on generating the different types of OWOM conversations. We use a dynamic hierarchical linear model (DHLM) for our analysis. The proposed model is compared with a dynamic linear model, vector autoregressive/system of equations model, and a generalized Bass model. Our estimation accounts for potential endogeneity in the key measures. Among the different OWOM measures, only the valence of recommendation OWOM is found to have a direct impact on sales; i.e., not all OWOM is the same. This impact increases over time. In contrast, the impact of attribute advertising and emotion advertising decreases over time. Also, consistent with prior research, we observe that rational messages (i.e., attribute-oriented advertising) wears out a bit faster than emotion-oriented advertising. Moreover, the volume of OWOM does not have a significant impact on sales. This suggests that, in our data, “what people say” is more important than “how much people say.” Next, we find that recommendation OWOM valence is driven primarily by the valence of attribute OWOM when the product is new and driven by the valence of emotion OWOM when the product is more mature. Our brand-level results help us classify brands as consumer driven or firm driven, depending on the relative importance of the OWOM and advertising measures, respectively.
Bayesian Approach with Pre- and Post-Filtering to Handle Data Uncertainty and Inconsistency in Mobile Robot Local Positioning
Authors: Abdulhafiz Waleed A. , Khamis Alaa
Published: January 2014

One of the important issues in mobile robots is finding the position of robots in space. This is normally achieved by using a sensor to locate the position of the robot. However, relying on more than one sensor and then using multisenor data fusion algorithms tends to be more reliable than just using a reading from a single sensor. If these sensors provide inconsistent data, catastrophic fusion may occur, and thus the estimated position of the robot obtained will be less accurate than if an individual sensor is used. This article uses an approach that relies on combining modified Bayesian fusion algorithm with Kalman filtering to estimate the position of a mobile robot. Two case studies are presented to prove the efficiency of the proposed approach in estimating the position of a mobile robot. Both scenarios show that combining fusion with filtering provides an accurate estimate of the location of the robot by handling the problem of uncertainty and inconsistency of the data provided by the sensors.
The Right to a Fair Fight
Authors: Anderson Jack
Published: January 2014

This article critically assesses the criminal law on consensual harm through an examination of the legality of fighting sports. The article begins by considering fighting sports such as bare-fisted prize fighting (dominant in the nineteenth century). It then, in historical chronology, examines the legality of professional boxing with gloves (dominant in the twentieth century). Doctrinally, the article reviews why and how, in a position adopted by the leading common law jurisdictions, fighting sports benefit from an application of the “well-established” category-based exceptions to the usual bodily harm threshold of consent in the criminal law. Centrally, fighting sports and doctrinal law on offenses against the person are juxtaposed against the theoretical boundaries of consent in the criminal law to examine whether and where the limit of the “right to be hurt” might lie. In sum, this article uses fighting sports as a case study to assess whether the criminal law generally can or should accommodate the notion of a fair fight, sporting or otherwise, predicated on the consent of the participants to the point that the individuals involved might be said, pithily, to have extended an open invite to harm.
Caenorhabditis elegans SWI/SNF Subunits Control Sequential Developmental Stages in the Somatic Gonad
Authors: Large Edward E , Mathies Laura D
Published: January 2014

The Caenorhabditis elegans somatic gonadal precursors (SGPs) are multipotent progenitors that give rise to all somatic tissues of the adult reproductive system. The hunchback and Ikaros-like gene ehn-3 is expressed specifically in SGPs and is required for their development into differentiated tissues of the somatic gonad. To find novel genes involved in SGP development, we used a weak allele of ehn-3 as the basis for a reverse genetic screen. Feeding RNAi was used to screen ∼2400 clones consisting of transcription factors, signaling components, and chromatin factors. The screen identified five members of the C. elegans SWI/SNF chromatin remodeling complex as genetic enhancers of ehn-3. We characterized alleles of 10 SWI/SNF genes and found that SWI/SNF subunits are required for viability and gonadogenesis. Two conserved SWI/SNF complexes, PBAF and BAF, are defined by their unique array of accessory subunits around a common enzymatic core that includes a catalytic Swi2/Snf2–type ATPase. Tissue-specific RNAi experiments suggest that C. elegans PBAF and BAF complexes control different processes during somatic gonadal development: PBRM-1, a signature subunit of PBAF, is important for normal SGP development, whereas LET-526, the distinguishing subunit of BAF, is required for development of a differentiated cell type, the distal tip cell (DTC). We found that the SWSN-4 ATPase subunit is required for SGP and DTC development. Finally, we provide evidence that C. elegans PBAF subunits and hnd-1/dHand are important for the cell fate decision between SGPs and their differentiated sisters, the head mesodermal cells.
The Afrikaner reaction to the singing of liberation songs in South Africa: The case of Julius Malema’s ‘Dubul’ ibhunu’ (Kill the Boer, Kill the Farmer) song
Authors: Twala Chitja
Published: January 2014

The article traces the impact and relevance of the singing of the liberation songs by members of the African National Congress (ANC) and the African National Congress Youth League (ANCYL) in South Africa’s new and fragile democratic dispensation. The study also highlights the reaction of the Afrikaner section of South Africa’s population, which claims that the singing of liberation songs, particularly ‘Dubul’ ibhunu’ promotes racism and hatred. Essentially, this challenge to the song by the Afrikaners was triggered by the singing of it in public by the then ANCYL President Julius Malema. The failure by Malema to refrain from singing this song led to taking the matter to the courts in order to ascertain the relevance of such songs in a democratic South Africa.
Informed actions: where to cost effectively manage multiple threats to species to maximize return on investment
Authors: Auerbach Nancy A. , Tulloch Ayesha I. T. , Possingham Hugh P.
Published: January 2014

Conservation practitioners, faced with managing multiple threats to biodiversity and limited funding, must prioritize investment in different management actions. From an economic perspective, it is routine practice to invest where the highest rate of return is expected. This return‐on‐investment (ROI) thinking can also benefit species conservation, and researchers are developing sophisticated approaches to support decision‐making for cost‐effective conservation. However, applied use of these approaches is limited. Managers may be wary of “black‐box” algorithms or complex methods that are difficult to explain to funding agencies. As an alternative, we demonstrate the use of a basic ROI analysis for determining where to invest in cost‐effective management to address threats to species. This method can be applied using basic geographic information system and spreadsheet calculations. We illustrate the approach in a management action prioritization for a biodiverse region of eastern Australia. We use ROI to prioritize management actions for two threats to a suite of threatened species: habitat degradation by cattle grazing, and predation by invasive red foxes (Vulpes vulpes). We show how decisions based on cost‐effective threat management depend upon how expected benefits to species are defined and how benefits and costs co‐vary. By considering a combination of species richness, restricted habitats, species vulnerability, and costs of management actions, small investments can result in greater expected benefit compared with management decisions that consider only species richness. Furthermore, a landscape management strategy that implements multiple actions is more efficient than managing only for one threat, or more traditional approaches that don't consider ROI. Our approach provides transparent and logical decision support for prioritizing different actions intended to abate threats associated with multiple species; it is of use when managers need a justifiable and repeatable approach to investment.
Relating the ABC and harmonic indices
Authors: Gutman Ivan , Zhong Lingping , Xu Kexiang
Published: January 2014

The atom-bond connectivity (ABC) index is a much-studied molecular structure
descriptor, based on the degrees of the vertices of the molecular graph.
Recently, another vertex-degree-based topological index - the harmonic index
(H) - attracted attention and gained popularity. We show how ABC and H are
related.
Characterization of energy conversion of multiferroic PFN and PFN:Mn
Authors: Kozielski Lucjan , Bochenek Dariusz
Published: January 2014

Characterization of energy conversion of multiferroic materials is concerned
with multifunctional properties of materials, a topic that is fascinating
from the scientific point of view and important for the modern technology.
The complex characterization of multiferroic structures suffers at present
from lack of a systematic experimental approach and deficiency of
multifunctional magnetoelectric properties testing capabilities. Compactness
and high frequency energy conversion capacity are the main reasons of
invention and improvement of sophisticated materials which are prepared for
high-speed computer memories and broadband transducer devices. As a
consequence, one can easily notice an intense search for new materials for
generation, transformation and amplification of magnetic and electric
energies. In this scenario, the combination of excellent piezoelectric and
magnetic properties makes lead iron niobate Pb(Fe1/2Nb1/2)O3 (PFN) an
attractive host material for application in integrated magnetoelectric energy
conversion applications. PFN multiferroic materials are attractive for
commercial electroceramics due to high value of dielectric permittivity and
magnetoelectric coefficients as well as relatively easy synthesis process.
However, synthesis of PFN ceramics is mostly connected with formation of the
secondary unwanted pyrochlore phase associated with dramatic decrease of
ferroelectric properties. The authors have successfully reduced this negative
phenomenon by Mn doping and finally present high piezoelectric and
magnetoelectric energy conversion efficiency in fabricated PMFN ceramics.
Permittivity and modulus spectroscopic study of BaFe0.5Nb0.5O3 ceramics
Authors: Kar Subrat , Kumar Pawan
Published: January 2014

Ba(Fe0.5Nb0.5)O3 (BFN) powder was synthesized in single perovskite phase by
conventional solid state reaction route and BFN ceramic was obtained by
uniaxial pressing and sintering at 1350?C. Complex immittance like:
permittivity and modulus spectroscopic formalism were simultaneously used to
explain dielectric behaviour of the ceramics. The activation energy
calculated from dielectric relaxation below 100?C was found to be ~ 0.19 eV.
The activation energy obtained from modulus spectra above 100?C was ~0.59 eV.
The space charge polarization model was used to explain the origin of
relaxation and ?giant? permittivity of BFN ceramics near room temperature.
Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal
Authors: Pozzilli Paolo , Raz Itamar , Peled Dana , Elias Dana , Avron Ann , Tamir Merana , Eren Rachel , Dagan Shlomo , Cohen Irun R.
Published: January 2014

OBJECTIVE

Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes.

RESEARCH DESIGN AND METHODS

A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson’s correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (∆AUC).

RESULTS

The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74–0.9). However, the correlations between the ∆AUC were much weaker (r = 0.39–0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4–11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose.

CONCLUSIONS

Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.
Numerical Evaluation of Sound Attenuation Provided by Periodic Structures
Authors: Martins Mário , Godinho Luís , Picado-Santos Luís
Published: January 2014

The use of periodic structures as noise abatement devices has already been the object of considerable research seeking to understand its efficiency and see to what extent they can provide a functional solu- tion in mitigating noise from different sources. The specific case of sonic crystals consisting of different materials has received special attention in studying the influence of different variables on its acoustic performance.

The present work seeks to contribute to a better understanding of the behavior of these structures by implementing an approach based on the numerical method of fundamental solutions (MFS) to model the acoustic behavior of two-dimensional sonic crystals. The MFS formulation proposed here is used to evaluate the performance of crystals composed of circular elements, studying the effect of varying dimen- sions and spacing of the crystal elements as well as their acoustic absorption in the sound attenuation provided by the global structure, in what concerns typical traffic noise sources, and establishing some broad indications for the use of those structures.
Effect of Binaural Stimulation on Attention and EEG
Authors: Crespo Adela , Recuero Manuel , Galvez Gerardo , Begoña Adrián
Published: January 2014

When two pure tones of slightly different frequency are presented separately to each ear, the listener perceives a third single tone with amplitude variations at a frequency that equals the difference between the two tones; this perceptual illusion is known as the binaural auditory beat (BB). There are anecdotal reports that suggest that the binaural beat can entrain EEG activity and may affect the arousal levels, although few studies have been published. There is a need for double-blind, well-designed studies in order to establish a solid foundation for these sounds, as most of the documented benefits come from self-reported cases that could be affected by placebo effect. As BBs are a cheap technology (it even exists a free open source programmable binaural- beat generator on the Internet named Gnaural), any achievement in this area could be of public interest. The aim in our research was to explore the potential of BBs in a particular field: tasks that require focus and concentration. In order to detect changes in the brain waves that could relate to any particular improvement, EEG recordings of a small sample of individuals were also obtained. In this study we compare the effect of different binaural stimulation in 7 EEG frequency ranges. 78 participants were exposed to 20-min binaural beat stimulation. The effects were obtained both quali- tative with cognitive test and quantitative with EEG analysis. Results suggest no significant statistical improvement in 20-min stimulation.
Technical Notes: Evaluation of Two Alternative Procedures for Measuring Airflow Resistance of Sound Absorbing Materials
Authors: Rey Romina del , Alba Jesus , Arenas Jorge P. , Ramis Jaime
Published: January 2014

It is well known that sound absorption and sound transmission properties of open porous materials are highly dependent on their airflow resistance values. Low values of airflow resistance indicate little resistance for air streaming through the porous material and high values are a sign that most of the pores inside the material are closed. The laboratory procedures for measuring airflow resistance have been stan- dardized by several organizations, including ISO and ASTM for both alternate flow and continuous flow. However, practical implementation of these standardized methods could be both complex and expensive. In this work, two indirect alternative measurement procedures were compared against the alternate flow standardized technique. The techniques were tested using three families of eco-friendly sound absorbent materials: recycled polyurethane foams, coconut natural fibres, and recycled polyester fibres. It is found that the values of airflow resistance measured using both alternative methods are very similar. There is also a good correlation between the values obtained through alternative and standardized methods.
Dietary intake of energy and selected nutrients and plasma lipid profile in young women and men with different levels of physical activity
Authors: Malara Marzena , Hübner-Woźniak Elżbieta
Published: January 2014

Study aim: The purpose was to assess dietary intake of energy and selected nutrients and plasma lipid profile in young women and men with different levels of physical activity.

Material and methods: The research included a total of 116 female and male students at the University of Physical Education who differed in their levels of physical activity. Analysis of the diets was based on 24-hour dietary interviews collected over 4 days prior to blood collection. Concentrations of total cholesterol (TC), HDL cholesterol (HDL-C), and triacylglycerol (TG) were measured in venous blood. In addition, the concentration of LDL cholesterol (LDL-C) and the ratios of TC / HDL-C and LDL-C/HDL-C were calculated.

Results: Women, regardless of their physical activity levels, were characterized by a significantly higher concentration of total cholesterol in plasma (4.8 and 4.5 mmol/L, respectively - in training participants; 4.7 and 4.3 mmol/L, respectively - in non-training participants), although their dietary intake of cholesterol was significantly lower in comparison with the corresponding groups of men (282.0 and 484.7 mg, respectively - in training participants; 252.6 and 400.2 mg, respectively - in non-training participants). A trend toward a worse lipid profile of training women and men compared with the corresponding groups of non-training participants was also observed.

Conclusions: Increased physical activity in the groups of training women and men was not a sufficient stimulus to induce positive changes in their lipid profiles. Nor can it be excluded that the observed differences were the result of diet, as dietary intake of cholesterol in the groups of training women and men was higher compared with the corresponding groups of non-training participants.
Einstein equation at singularities
Authors: Stoica Ovidiu-Cristinel
Published: January 2014

Einstein’s equation is rewritten in an equivalent form, which remains valid at the singularities in some major cases. These cases include the Schwarzschild singularity, the Friedmann-Lemaître-Robertson-Walker Big Bang singularity, isotropic singularities, and a class of warped product singularities. This equation is constructed in terms of the Ricci part of the Riemann curvature (as the Kulkarni-Nomizu product between Einstein’s equation and the metric tensor).
Pre Participation Examination: Tool for Cardiovascular Screening of Competitive Athletes
Authors: Kaur Badwal Kulroop
Published: January 2014

The heart of an athlete has instilled inquisitiveness in many researchers, clinicians since a century. It is now well established that tedious physical training results in significant changes in cardiac structure and function. The recent increases in the number of people participating in recreational exercises and sports competitions have led to growing number of people exhibiting such changes. So the pre-participation screening becomes an important tool for non invasive examination and for diagnostic purposes. The main purpose of this consensus document is to reinforce the principle of the need for pre-participation medical clearance of all competitive athletes involved in organized sports programs, on the basis of (i) systematic screening by 12-lead ECG (in addition to history and physical examination) to identify hypertrophic cardiomyopathy - the leading cause of sportsrelated sudden death - and to prevent athletic field fatalities; (ii) transthoracic echocardiography with the potential ability of screening ability in detecting other lethal cardiovascular diseases.
Habitat use of a critically‐endangered species in a predator‐free but degraded reserve in Australia
Authors: Winnard Amy L. , Stefano Julian Di , Coulson Graeme
Published: January 2014

The success of species reintroduction programmes depends on many factors, including habitat quality and predator occurrence at release locations. For the critically endangered eastern barred bandicoot Perameles gunnii in Australia, successful releases have been achieved only in the absence of predation by the introduced red fox Vulpes vulpes. However, few fox‐free sites exist, but those that are fox free may have low habitat suitability, potentially leading to reintroduction failure. We studied a reintroduced population of eastern barred bandicoots at Mt Rothwell, a 420‐ha fox‐free reserve which appeared to have a degraded foraging range and a lack of nesting material due to overgrazing by marsupial herbivores. We quantified habitat use and measured several variables representing movement distances and nest use. Bandicoots foraged in open grassy areas and nested at sites containing high values of litter, lateral cover and concealment cover. Mean (± SE) home ranges (37.2 ha ± 11.8), daily movement distances (494.6 m ± 32.5) and distances between consecutive nests (122.6 m ± 29.0) were large for males. On average, the length of stay at each nest (2.8 days ± 0.4) was longer than previously recorded values for males, and 13.2% of the nests were used by at least two individuals, suggesting that nesting opportunities were limited. Despite behaviour indicating a low resource base, bandicoots appeared to be surviving and reproducing in our study area, indicating a capacity to live in structurally simple habitat in the absence of predators. Our results are consistent with predator exclusion being a critical factor for successful bandicoot reintroduction.
The incidence of postoperative hyponatremia and associated neurological sequelae in children with intracranial neoplasms
Authors: Williams Cydni N. , Belzer Jennifer S. , Riva-Cambrin Jay , Presson Angela P. , Bratton Susan L.
Published: January 2014

Object

Intracranial tumors are common pediatric neoplasms and account for substantial morbidity among children with cancer. Hyponatremia is a known complication of neurosurgical procedures and is associated with higher morbidity among neurosurgical patients. The authors aimed to estimate the incidence of hyponatremia, identify clinical characteristics associated with hyponatremia, and assess the association between hyponatremia and patient outcome among children undergoing surgery for intracranial tumors.

Methods

This is a retrospective cohort study of children ranging in age from 0 to 19 years who underwent an initial neurosurgical procedure for an intracranial tumor between January 2001 and February 2012. Hyponatremia was defined as serum sodium ≤ 130 mEq/L during admission.

Results

Hyponatremia during admission occurred in 39 (12%) of 319 patients and was associated with young age and obstructive hydrocephalus (relative risk [RR] 2.9 [95% CI 1.3–6.3]). Hyponatremic patients were frequently symptomatic; 21% had seizures and 41% had altered mental status. Hyponatremia was associated with complicated care including mechanical ventilation (RR 4.4 [95% CI 2.5–7.9]), physical therapy (RR 4 [95% CI 1.8–8.8]), supplemental nutrition (RR 5.7 [95% CI 3.3–9.8]), and infection (RR 5.7 [95% CI 3.3–9.5]). Hyponatremic patients had a 5-fold increased risk of moderate or severe disability on the basis of their Pediatric Cerebral Performance Category score at discharge (RR 5.3 [95% CI 2.9–9.8]). Obstructive hydrocephalus (adjusted odds ratio [aOR] 3.24 [95% CI 1.38–8.94]) and young age (aOR 0.92 [95% CI 0.85–0.99]) were independently associated with hyponatremia during admission. Hyponatremia was independently associated with moderate or worse disability by Pediatric Cerebral Performance Category score at discharge (aOR 6.2 [95% CI 3.0–13.03]).

Conclusions

Hyponatremia was common, particularly among younger children and those with hydrocephalus. Hyponatremia was frequently symptomatic and was associated with more complicated hospital courses. Hyponatremia was independently associated with worse neurological outcome when adjusted for age and tumor factors. This study serves as an exploratory analysis identifying important risk factors for hyponatremia and associated sequelae. Further research into the causes of hyponatremia and the association with poor outcome is needed to determine if prevention and treatment of hyponatremia can improve outcomes in these children.
Spinal dural arteriovenous shunt presenting with intramedullary hemorrhage
Authors: Narisawa Ayumi , Endo Toshiki , Sato Kenichi , Watanabe Mika , Takahashi Akira , Tominaga Teiji
Published: January 2014

The authors report on a 49-year-old man with a thoracic spinal dural arteriovenous shunt (dAVS) in which rupture of a varix caused intramedullary hemorrhage. In the literature, patients with a thoracic dAVS predominantly present with congestive myelopathy; however, the patient featured in this report presented without increased deep tendon reflexes or muscle weakness, but instead with intermittent stabbing chest pain and paresthesia. Magnetic resonance images and angiograms demonstrated tortuous enlargement and the formation of a varix-like structure of the draining veins, features compatible with those of high-flow angiopathy. Recognition of this phenomenon is important in thoracic dAVS because intramedullary hemorrhage dramatically degrades outcome. A high index of clinical suspicion can prevent a similar case of thoracic dAVS from progressing to intramedullary hemorrhage.
New Professionalism Challenges in Medical Training: An Exploration of Social Networking
Authors: Kesselheim Jennifer C. , Batra Maneesh , Belmonte Frank , Boland Kimberly A. , McGregor Robert S.
Published: January 2014

Background

Innovative online technology can enhance the practice of medicine, yet it also may be a forum for unprofessional behavior.

Objective

We surveyed program directors regarding their perceptions and experiences with residents' use of social networking sites (SNS).

Methods

In September 2011, we sent an online survey to program directors and associate program directors of pediatrics residency programs within the United States who are members of the Association of Pediatric Program Directors.

Results

A total of 162 program directors or associate program directors (representing 50% of residency programs) responded to the survey. One-third of respondents are “very familiar” with SNS and 23% use them “daily or often.” Most respondents (70%) rated “friending” peers as “completely appropriate,” whereas only 1% of respondents rated “friending” current or past patients as “completely appropriate.” More than one half of respondents believe inappropriate behavior on SNS is “somewhat” or “very” prevalent, and 91% are “somewhat” or “very” concerned that the prevalence of inappropriate behavior on SNS may increase. The most commonly reported problematic online activity was posting inappropriate comments about the workplace. Posting of inappropriate comments about self, patients, and staff also was observed. Residency programs commonly educate trainees about SNS during intern orientation (45%), or using written guidelines (29%) and ad hoc remediation (16%).

Conclusions

As educators teach trainees principles of online professionalism, appropriate use of SNS needs to be included in the training process. Curricular efforts may be hindered by some program directors' lack of familiarity with SNS.
Evaluating the embedded energy in real water loss
Authors: Aubuchon Craig P , Roberson J. Alan
Published: January 2014

This research considers the issue of water distribution and aging infrastructure within the context of the water–energy nexus. Because it takes energy to treat and distribute drinking water, infrastructure repair that reduces real water losses matters for both water and energy conservation efforts. The current research estimates the embedded energy in real water losses, and suggests that water systems should quantify these potential savings when developing future capital improvement plans. The current research uses the best available data from a representative cross‐section of water systems, including estimated water losses and publicly available data on energy consumption. Increased future energy costs and increased pressures for energy and water efficiencies will likely bolster the priority for distribution system improvements to decrease real water losses.
Preference Trials
Authors: Campbell Marion K. , Torgerson David J.
Published: January 2014

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.
Prevention Trials
Authors: Prentice Ross L.
Published: January 2014

Randomized controlled trials provide the gold standard for assessing the health benefits and risks of preventive treatments or interventions. Such trials typically need to be very large‐scale and long‐term. Hence, cost and logistic considerations imply that few such trials can be conducted, and there is a need for careful hypothesis development and preliminary testing, prior to the initiation of a full‐scale disease prevention trial. Aspects of the design, conduct monitoring and analysis of prevention trials are reviewed, along with a discussion of differences from therapeutic trials, and of the interplay with observational studies. The National Institutes of Health‐sponsored Women's Health Initiative, which includes both a multi‐faceted prevention trial, and a large cohort study, among postmenopausal women, provides an illustration of prevention trial considerations and trade‐offs.
Primary Efficacy Endpoint
Authors: Follmann Dean A
Published: January 2014

At its core, a clinical trial is designed to test a specific primary hypothesis. The primary efficacy endpoint in a clinical trial is a clinical or laboratory outcome measured in an individual after randomization that allows one to test the primary hypothesis and provides the means of assessing whether a therapy is effective compared with its control. A primary endpoint can be measured once or repeatedly over time, or may comprise several kinds of individual measurements. Once a primary endpoint is selected, statistical methods of analysis to test the primary hypothesis can be determined and sample size calculations can be performed to ensure the trial is properly powered. Because of the key role of the primary endpoint in the design and analysis of a trial, it is critical that it be chosen carefully. A primary efficacy endpoint must be precisely specified in advance and should(1)address the primary objective,(2)be ascertainable in all patients,(3)be “fair” to each study arm,(4)have demonstrated or accepted relevance for the population and intervention(s) of the trial, and(5)be sensitive to meaningful changes in a patient's health.
Repeated Measurements
Authors: Verbeke Geert , Lesaffre Emmanuel
Published: January 2014

Repeated measures are obtained whenever an outcome is measured repeatedly within a set of units. The fact that observations from the same unit, in general, will not be independent poses particular challenges to the statistical procedures used for the analysis of such data. The current article is dedicated to an overview of frequently used statistical models for the analysis of repeated measurements, with emphasis on model formulation and parameter interpretation.
Screening, Models of
Authors: Stevenson Chris
Published: January 2014

This article describes models for disease screening and how they have developed in recent years. The discussion focuses on screening for cancer, because most of the methodological advances in screening design and evaluation have concerned cancer screening. The first part of the article describes the characteristics of these models and illustrates them with a discussion of a simple screening model. The second part describes the development, strengths, and weaknesses of the two main types of screening model—analytic and simulation models—with a particular focus on microsimulation models. The third part discusses model fitting and validation, and the final part briefly describes models for diseases other than cancer—in particular, models for screening for infectious diseases—and discusses the current state and possible future directions for models of disease screening.
Subgroup
Authors: Wittes Janet
Published: January 2014

Randomized clinical trials are usually designed to show an effect of treatment in the study population at large. Trials rarely have sufficient statistical power to measure reliably the effect of a treatment within a subgroup of that population. They are even less likely to provide reliable information on whether the effect of a treatment differs from subgroup to subgroup. This article defines various terms related to analysis of subgroups. It distinguishes between subgroups defined on the basis of baseline variables from “improper” subgroups defined on the basis of variables measured after randomization. It also discusses hypotheses defined a priori and those identified after the results have emerged. It emphasizes that random variation arising from small sample sizes can lead to unrealistically large or small observed effects and warns investigators to interpret findings from subgroups with caution.
The FDA and Regulatory Issues
Authors: Rzeszotarski W. Janusz
Published: January 2014

A brief outline of information that is available on the Web pertinent to the FDA and regulatory issues. The process of new drug approval and its continuous modification reflects both the progress of science and the globalization of the world's economy. The reader is encouraged to follow the changes by constant monitoring of the FDA and the industry sites dedicated to these issues. The history of drug regulation in the United States, the evolving structure of the FDA, the steps to be taken in the process of obtaining the approval to market the new molecular entity, and the post‐approval requirements are briefly described.
Treatment Interruption
Authors: Grund Birgit
Published: January 2014

Interruption of active drug treatment in clinical trials can be classified broadly as therapeutic treatment interruption (TI), in which the potential therapeutic benefit of supervised interruption of treatment is investigated, and analytic TI, in which participants are randomized to stopping versus continuing active treatment; the TI arm serves as control group. Design issues for therapeutic TI trials are discussed in the example of a trial in HIV/AIDS.

Analytic TIs are used in therapeutic HIV vaccine trials, in randomized discontinuation designs, and in other situations. The use of a randomized discontinuation design for a Phase II drug trial in cancer is discussed.
Absolute Risk Reduction
Authors: Newcombe Robert G.
Published: January 2014

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.
Accelerated Approval
Authors: Cabanilla Louis A. , Milne Christopher P.
Published: January 2014

In 1992, the Food and Drug Administration (FDA) promulgated regulations for the Accelerated Approval program, which allowed drugs to gain approval based on unvalidated surrogate endpoints, or an effect on a clinical endpoint other than survival, or approval with restricted distribution. Initially, the program was primarily targeted at AIDS and cancer treatments, but it is now available for a wide array of diseases, and it has grown beyond small molecules to encompass biologic products, vaccines, and other product areas. Because of the severity of the illnesses being addressed and the potential for a “meaningful clinical benefit,” the FDA is generally willing to accept a higher risk to benefit ratio for an accelerated approval to provide earlier treatment for patients despite the lack of definitive evidence of the ultimate clinical benefit. Although a drug that is given accelerated approval might reach the market, the company sponsoring the drug is required to complete the necessary research to determine efficacy with a “Phase IV” study with “due diligence.” A problem with the definition of diligence, as well as enforcement mechanisms, has lead to some contention about the level of compliance by the drug industry. Despite these issues, the program alone, or in concert with other FDA approval programs, has to date brought some 50 lifesaving drugs to market months or years faster than would have happened through the traditional process. This information, together with advances in the science and technology of the clinical evaluation of biopharmaceuticals and the more powerful voice of patient advocacy in determining regulatory agency policy, ought to ensure that accelerated approval will expand its reach both therapeutically and geographically.
Aligned Rank Test
Authors: McNeil Rebecca B. , Woolson Robert F.
Published: January 2014

Aligned rank tests are an intuitive rank‐based approach to the evaluation of an experimental treatment effect in blocked or stratified data. Their interblock ranking foundation yields an efficiency advantage relative to comparable tests constructed from intrablock rankings such as Friedman's test. Both exact and asymptotic tests of the null hypothesis are available with this approach. We present a general overview of the history and construction of aligned rank tests, and provide an example in selected data from a clinical trial of high‐dose vitamin D supplementation.
Analysis of VarianceANOVA
Authors: Kaufmann Jörg , Schering AG
Published: January 2014

The development of analysis of variance (ANOVA) methodology has in turn had an influenced on the types of experimental research being carried out in many fields. ANOVA is one of the most commonly used statistical techniques, with applications across the full spectrum of experiments in agriculture, biology, chemistry, toxicology, pharmaceutical research, clinical development, psychology, social science, and engineering. The procedure involves the separation of total observed variation in the data into individual components attributable to various factors as well as those caused by random or chance fluctuation. It allows performing hypotheses tests of significance to determine which factors influence the outcome of the experiment. However, although hypothesis testing is certainly a very useful feature of the ANOVA, it is by no means the only aspect. The methodology was originally developed by Sir Ronald A. Fisher, the pioneer and innovator of the use and applications of statistical methods in experimental design who coined the name “Analysis of Variance – ANOVA.”
Assessment Bias
Authors: Gøtzsche Peter C.
Published: January 2014

Assessment bias in a clinical trial occurs if bias in the assessment of the outcome exists. It is also called ascertainment bias, diagnostic bias, or detection bias. A major cause of assessment bias is lack of blinding. Other problems relate to differential identification of harmless or false‐positive cases of disease, bias in assessment of disease‐specific mortality, the use of composite outcomes, competing risks, timing of the assessments, and bias in assessment of harms.
Biological Assay, Overview
Authors: Sen Pranab K.
Published: January 2014

Biological essay (or “bioassay”), in its classical form, is concerned with the measurement of the concentration of an active ingredient in a test preparation, by estimation of its potency relative to that of a standard preparation. Assays, usually by animal experimentation, form an essential tool of biological standardization. Standard designs and methods of analysis are described here, including stochastic approximation, radioimmunoassays, semiparametric and nonparametric methods, and bioequivalence studies. In a broader sense, Bioassay refers to experiments, with biological units, to detect possible dose–response (or toxicity‐adverse effect) relationships. Underlying toxicodynamics (and/or pharmacodynamics) and toxicokinetics (and/or pharmacokinetics), possibly in conjunction with toxicogenomics (and/or pharmacogenomics) may render such studies statistically quite different from conventional biometric studies. Some relevant approaches are considered here.
Bootstrap
Authors: Hesterberg Tim
Published: January 2014

This article provides an introduction to the bootstrap. The bootstrap provides statistical inferences—standard error and bias estimates, confidence intervals, and hypothesis tests—without assumptions such as normal distributions or equal variances. As such, bootstrap methods can be remarkably more accurate than classic inferences based on normal ortdistributions. The bootstrap uses the same basic procedure regardless of the statistic being calculated, without requiring the use of application‐specific formulae.

This article may provide two big surprises for many readers. The first is that the bootstrap shows that commontconfidence intervals are woefully inaccurate when populations are skewed, with one‐sided coverage levels off by factors of two or more, even for very large samples. The second is that the number of bootstrap samples required is much larger than generally realized.
Clinical Data Management
Authors: McBride Ruth
Published: January 2014

Clinical data management is data management systems and process focused on providing clean, current and reliable data to support clinical research, especially for clinical trials. Computerized systems have been used since the early 1960's. Current clinical data management systems vary. Many, but not all clinical trials use electronic data capture to collect data from clinical research sites. Efforts are underway to standardize the way clinical data are organized.
Confounding
Authors: Greenland Sander
Published: January 2014

The word
confounding
has been used to refer to at least three distinct concepts. In the oldest usage, confounding is a
bias
in estimating causal effects (
see
Causation
). This bias is sometimes informally described as a mixing of effects of extraneous factors (called
confounders
) with the effect of interest. This usage predominates in nonexperimental research, especially in epidemiology and sociology. In a second and more recent usage, confounding is a synonym for noncollapsibility (
see
Collapsibility
), although this usage is often limited to situations in which the parameter of interest is a causal effect. In a third usage, originating in the
experimental‐design
literature, confounding refers to inseparability of main effects and
interactions
under a particular design. The term
aliasing
is also sometimes used to refer to the latter concept; this usage is common in the
analysis of variance
literature.
Crossover Design
Authors: Kenward Michael G.
Published: January 2014

In a crossover design, each subject is randomized to a sequence of treatments with the aim of comparing the effect of an individual treatment assignment. Such trials are restricted to fairly stable conditions and treatments with reversible effects. When within‐subject dependence of the outcome is high, such designs can be much more efficient than a parallel‐group study with the same number of subjects. However, because randomization applies to the sequences, not the individual treatments, the justification for the analysis of data from such trials depends more on model‐based assumptions than a typical parallel‐group study. The most commonly used crossover design is the so‐called two‐period, two‐treatment design, in which subjects are randomized to one of two sequences, A then B or B then A. Provided it can be assumed that the consequences of treatment allocation in the first period does not bias the treatment comparison in the second period (carryover), the analysis of such trials is very simple. It turns out that in most trials there will be very little information in the data on possible carryover, and therefore no useful statistical procedure exists either for its assessment or for adjustment for it. As a consequence, prior knowledge and adequate washout periods need to be used to justify the analysis in such settings. Higher order designs with more than two periods and more than two sequences exist for both the two‐treatment setting and for more than two treatments. Efficient designs can be constructed that allow adjustment for carryover, but only when it is expressed in particular, limited, mathematical forms. Data from crossover designs are examples of conventional repeated measures and analyses can be taken from the range of tools available for these, both with continuous and discrete outcomes.
Dose Ranging Crossover Designs
Authors: Patterson Scott D. , Jones Byron , Zariffa Névine
Published: January 2014

Dose ranging trials are used frequently in drug development to learn about dose response for both desirable and undesirable effects and to provide sponsors with confidence that investment in confirmatory trials for market access is likely to be successful. The design of crossover studies and analysis of data that develops from such crossover trials are discussed.