Key Decision Points Research Articles

Implementation of a Bayesian adaptive design in a proof of concept study

With increased costs of drug development the need for efficient studies has become critical. A key decision point on the development pathway has become the proof of concept study. These studies must provide clear information to the project teams to enable decision making about further developing a drug candidate but also to gain evidence that any effect size is sufficient to warrant this development given the current market environment. Our case study outlines one such proof of concept trial where a new candidate therapy for neuropathic pain was investigated to assess dose-response and to evaluate the magnitude of its effect compared to placebo. A Normal Dynamic Linear Model was used to estimate the dose-response--enforcing some smoothness in the dose-response, but allowing for the fact that the dose-response may be non-monotonic. A pragmatic, parallel group study design was used with interim analyses scheduled to allow the sponsor to drop ineffective doses or to stop the study. Simulations were performed to assess the operating characteristics of the study design. The study results are presented. Significant cost savings were made when it transpired that the new candidate drug did not show superior efficacy when compared placebo and the study was stopped.

Using 2-domain partitioned OBDD data structure in an enhanced symbolic simulator

In this article, we propose a symbolic simulation method where Boolean functions can be efficiently manipulated through a 2-domain partitioned OBDD data structure. The functional partition is applied by automatically exploring the key decision points implicitly built inside a circuit. The partition can help to significantly reduce the OBDD sizes, solving problems that could not be solved with monolithic OBDD data structure. We demonstrate the performance of the approach through the symbolic simulation of several benchmark circuits with complex control logics and datapath. The symbolic simulation based on 2-domain partitioned OBDD can be also applied in equivalence checking. It can generate the signature of functions to identify the critical partition points in the optimized gate-level netlist.

Deception Research Involving Children: Ethical Practices and Paradoxes

This commentary draws on the thoughtful contemplation and innovative procedures described in the special section articles as well as current professional codes and federal regulations to highlight ethical practices and paradoxes of deception research involving children. The discussion is organized around 4 key decision points for the conduct of responsible deception research involving children: (a) evaluating the scientific validity and social value of deception research within the context of alternative methodologies, (b) avoiding and minimizing experimental risk, (c) the use of child assent procedures as questionable ethical safeguards, and (d) debriefing as both remedy and risk.

Comparison of a Miniaturized Shake-Flask Solubility Method with Automated Potentiometric Acid/Base Titrations and Calculated Solubilities

Solubility is one of the most important parameters for lead selection and optimization during drug discovery. Its determination should therefore take place as early as possible in the process. Because of the large numbers of compounds involved and the very low amounts of each compound available in the early development stage, it is highly desirable to measure the solubility with as little compound as possible and to be able to improve the throughput of the methods used. In this work, a miniaturized shake‐flask method was developed and the solubility results were compared with those measured by semiautomated potentiometric acid/base titrations and computational methods for 21 poorly soluble compounds with solubilities mostly in the range 0.03–30 μg/mL. The potentiometric method is very economical (approximately 100 μg of a poorly soluble compound is needed) and is able to create a pH/solubility profile with one single determination, but is limited to ionizable compounds. The miniaturized shake‐flask method can be used for all compounds and a wide variety of media. Its precision and throughput proved superior to the potentiometric method for very poorly soluble compounds. Up to 20 compounds a week can be studied with one set‐up. Calculated solubility data seem to be sufficient for a first estimate of the solubility, but they cannot currently be used as a substitute for experimental measurements at key decision points in the development process. © 2004 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:1–16, 2005

Toward Differentiated Decision-Making: Family Systems Theory with the Homeless Clinical Population

The clinical treatment of the homeless population typically focuses on issues of mental illness and drug/alcohol dependency. This treatment, however, does not address the problems of the homeless who are not mentally ill or those without a dependency problem. Because of the nature of the presenting problems of the homeless, Bowen family systems theory provides an appropriate framework from which to view these cases. An effective framework of therapy using Bowen's family systems theory to work with the homeless clinical population is described. The four phases of this treatment framework include connection, assessment, treatment/consolidation, and crisis intervention. Through these phases, therapists work to help the homeless client identify emotional patterns and to make different decisions at key decision points, thereby breaking the pattern of behavior leading up to and maintaining homelessness. Clinical examples of each phase are provided.

The association of donor center characteristics with attrition from the national marrow donor registry

The National Marrow Donor Program (NMDP) has approximately 5 million registered potential donors and continues to add more than 30,000 new recruits to the registry monthly. However, more than 30% of potential donors are not available or decline to donate at key decision points in the donation process. Although previous researchers have examined the association of individual donor characteristics with attrition from the registry, no published studies have investigated the role of donor center characteristics or features of the donor centers' environment on attrition rates. Donor center coordinators from 72 NMDP centers completed questionnaires that included items regarding donor center location and organization, recruitment strategies, and registry management. Center-specific registry composition data and attrition rates were gathered from the NMDP database. Analyses indicated that higher attrition was found at larger centers that needed more center staff and volunteers to deal with larger workloads and more DR-typing requests. Attrition was also higher among centers located in highly populated, urban environments, with larger minority and less stable populations. The results indicate that the NMDP may need to tailor donor center retention expectations to account for certain unchangeable characteristics (e.g., center size and population stability) and to develop internal strategies to address the unique characteristics of each donor center (e.g., current performance level or improvement needs).

Managing skin and soft tissue infections: expert panel recommendations on key decision points

Managing skin and soft tissue infections: expert panel recommendations on key decision points

Applicability of the World Commission on Dams' recommendations for public financial institutions: a case for Japanese yen loan assistance

AbstractThe World Commission on Dams (WCD) published ‘Dams and Development’ as its only and final report in November 2000. Identifying ‘core values’ and ‘strategic priorities’, the report proposed ‘internationally acceptable criteria and standards’. Despite the fact that the WCD itself did not intend that the report be used as a blueprint, many non‐governmental organizations strongly support the report and the criteria and guidelines recommended in the report, and demand that they be adopted in their current form by funding organizations. The WCD criteria and guidelines were found to have several ‘methodological’ problems, and it appears impossible to apply the recommended criteria and guidelines as they stand. This study examines the applicability of the WCD criteria and guidelines for public financing institutes involved in overseas development assistance and proposes necessary measures to increase their applicability in order to realize core values and strategic priorities. The character of and relationships among key decision points, strategic priorities, criteria, and guidelines should be clarified. Then, this study examines the applicability of the WCD recommendations for Japanese public financial institutions, as Japan has nearly become the sole bilateral donor providing financial assistance (loans) for large dam construction projects. The public financial institution can only be mandated to check the legal status of the decisions made regarding Stages 1 and 2 which are the first two of the five successive stages from the planning to the operation of the dam project. Needs assessment and alternative selection are expected to be conducted at Stage 1 and 2 respectively. The Japan Bank for International Cooperation (JBIC), which deals with the Japanese concessional yen loan, and the Japan International Cooperation Agency (JICA), which is in charge of technical assistance, are featured in this study. As for the Japanese concessional yen loan assistance, there are other inherent problems for adopting the recommendations. First, it is not clear which government agency officially and substantially carries the decision‐making responsibility. Second, JBIC may be involved only when Stage 2 has been completed, and it should be decided and clarified to what extent the Japanese government, as well as JIBC and JICA, should be involved in Stages 1 and 2 (2A: intensive studies on alternatives) of a project for which funding is requested. These issues need to be solved if the Japanese government wishes to adopt the recommendations. Copyright © 2003 John Wiley & Sons, Ltd.

The diffusion of a pediatric care innovation in a large urban nonprofit health care system

AbstractThis article documents and analyzes the diffusion of an innovation in pediatric primary care, the Healthy Steps for Young Children Program, in a large health care system, Advocate Health Care in Chicago. We use Everett Rogers's model (1995) for the diffusion of innovations to provide the framework for this discussion of the key decision points, challenges, obstacles, critical success factors, and other factors that have contributed to the ongoing expansion efforts in Advocate. In so doing we chronicle the progression of Healthy Steps from Advocate's initial decision to pilot the program at five pediatric sites to its decision to expand the approach broadly within the Advocate system. Rogers's model facilitates both description and the development of useful guides for future innovations within a broad range of nonprofit organizations.

An approach for the quantitative consideration of genetic polymorphism data in chemical risk assessment: examples with warfarin and parathion.

In recent years, a great deal of research has been conducted to identify genetic polymorphisms. One focus has been to characterize variability in metabolic enzyme systems that could impact internal doses of pharmaceuticals or environmental pollutants. Methods are needed for using this metabolic information to estimate the resulting variability in tissue doses associated with chemical exposure. We demonstrate here the use of physiologically based pharmacokinetic (PBPK) modeling in combination with Monte Carlo analysis to incorporate information on polymorphisms into the analysis of toxicokinetic variability. Warfarin and parathion were used as case studies to demonstrate this approach. Our results suggest that polymorphisms in the PON1 gene, that give rise to allelic variants of paraoxonase, which is involved in the metabolism of paraoxon (a metabolite of parathion), make only a minor contribution to the overall variability in paraoxon tissue dose, while polymorphisms in the CYP2C9 gene, which gives rise to allelic variants of the major metabolic enzyme for warfarin, account for a significant portion of the overall variability in (S)-warfarin tissue dose. These analyses were used to estimate chemical-specific adjustment factors (CSAFs) for the human variability in toxicokinetics for both parathion and warfarin. Implications of alternatives in the calculation of CSAFs are explored. Key decision points for applying the PBPK-Monte Carlo approach to evaluate toxicokinetic variability for other chemicals are also discussed.

Human Performance Modeling and Decision Analysis in a Concept Crew Workstation

As part of the effort to evaluate the performance of soldiers operating in the Vetronics Testbed Technology (VTT), a human performance model of operator processes and tasks was developed. The purpose of this effort was to gather insight into operator workload constraints, points of operator overload due to task demands, and key decision-making points and strategies employed by the operators. Operator performance was modeled when the operators were confronted with the task of controlling multiple experimental unmanned ground vehicles (XUV) in addition to performing standard Command and Control (C2) operations. The model was built using the Improved Performance Research Integration Tool (IMPRINT). Development began with a task decomposition of the current VTT system and operator control unit (OCU) and was decomposed to the button-push level of operator interaction with the unit. Next, several operational scenarios were developed to drive the simulated operator actions in the OCU and obtain measures of performance. Finally, a decision-making architecture was implemented in the model to examine points where intelligent agents and system automation could potentially aid in reducing operator cognitive demands.

PLANNING PROCESS FOR PUBLIC PARTICIPATION IN REGIONAL WATER RESOURCES PLANNING1

ABSTRACT: The state of Texas passed legislation in 1997 that established a process for developing a 50‐year state water plan through a bottoms‐up approach involving representation from at least 11 recommended special interest groups. Moorhouse Associates Inc. was contracted to develop and implement a Public Participation Plan for the South Central Texas Region. The two goals of the public process were to take planning information out to the public and to provide a format for bringing the public opinion back to the planning group. The overall goal of the project was to provide public input throughout the planning process that will facilitate the development of a water plan that is widely accepted by the public. By using county government to establish focus groups, participation was encouraged from all of the twenty‐one counties in the region. The tools used in the process included an Internet site, surveys, focus groups, public meetings, community group presentations, media communications, and newspaper clippings. The public participation process as implemented, maintained communication throughout the planning process and at key decision points. This ongoing communication helped alleviate an initial uneasiness with the integrated resource planning approach.

A Plan for the Development of Fusion Energy

This is the final report of a panel set up by the U.S. Department of Energy (DOE) Fusion Energy Sciences Advisory Committee (FESAC) in response to a charge letter dated September 10, 2002 from Dr. Ray Orbach, Director of the DOE's Office of Science. In that letter, Dr. Orbach asked FESAC to develop a plan with the end goal of the start of operation of a demonstration power plant in approximately 35 years. This report, submitted March 5, 2003, presents such a plan, leading to commercial application of fusion energy by mid-century. The plan is derived from the necessary features of a demonstration fusion power plant and from the time scale defined by President Bush. It identifies critical milestones, key decision points, needed major facilities and required budgets. The report also responds to a request from DOE to FESAC to describe what new or upgraded fusion facilities will “best serve our purposes” over a time frame of the next twenty years.

Who's in charge of quality? The governance issues in quality assurance

This essay, exploring the general question of how quality assurance has changed the relationship between government and higher education, discusses two important issues of governance: what is the proper role of government? and what are the appropriate forms of academic involvement in decisions about quality assurance? It seeks to reaffirm some principles of shared governance in ensuring quality and suggests how these principles could apply to key decision points in quality assurance.

Emerging technologies to support indirect procurement: two case studies from the petroleum industry

This paper discusses the use of emerging Internet technologies to support indirect (non-production oriented) procurement processes. We provide an overview of objectives and available technologies and outline some of the critical success factors and key decision points. Two case studies from the Petroleum Industry help demonstrate the concepts.

Serum Prealbumin in Measurement of Nutrition Status and Monitoring Nutrition Support Outcome in a Sub Acute Skilled Nursing Unit

Itt is estimated that 30–85% of residents entering skilled nursing units are at significant nutritional risk. The effects of MNT for residents in a subacute skilled nursing unit were studied. All residents received a comprehensive nutritional assessment upon admission to the unit and were evaluated for malnutrition. parameters to measure malnutrition include: residents < 90% healthy weight range based on metropolitan height and weight tables for adults, significant weight loss of 5% in 30 days, 7.5% in 90 days, 10% in 180 days, albumin level < 3.0mg/dl, prealbumin level < 16mg/dl, average p.o. intake of 25–50%, and dermal wounds.Residents exhibiting some form of malnutrition (n=204)/75% of admissions were placed in the study and prealbumin levels were obtained on admission and at five day intervals via standing order. The average length of stay for the unit is 12–14 days. residents were reassessed every 4–6 days with tracking of prealbumin and albumin levels. % usual body weight and % ideal body weight. specific nutrition therapy intervention was documented and adjusted based on need or as triggered by key decision points at any interval specified, ie. lab value changes, food consumption changes, change in diet therapy or weight change.Although disease process in this population, including renal and hepatic failure, may contraindicate improvement of nutritional status, the majority of residents (68%) showed significant improvement in visceral protein stores based on a 5mg/dl increase in prealbumin within 5 days.It is concluded that prealbumin is useful as a baseline value as well as the best measure of the effects of nutritional intervention.

Thalamocortical Axons Are Influenced by Chemorepellent and Chemoattractant Activities Localized to Decision Points along Their Path

Thalamocortical axons (TCAs), which originate in dorsal thalamus, project ventrally in diencephalon and then dorsolaterally in ventral telencephalon to their target, the neocortex. To elucidate potentially key decision points in TCA pathfinding and hence the possible localization of guidance cues, we used DiI-tracing to describe the initial trajectory of TCAs in mice. DiI-labeled TCAs extend ventrally on the lateral surface of ventral thalamus. Rather than continuing this trajectory onto the lateral surface of the hypothalamus, TCAs make a sharp lateral turn into ventral telencephalon. This behavior suggests that the hypothalamus is repulsive and the ventral telencephalon attractive for TCAs. In support of this hypothesis, we find that axon outgrowth from explants of dorsal thalamus is biased away from hypothalamus and toward ventral telencephalon when cocultured at a distance in collagen gels. Thein vivoDiI analysis also reveals a broad cluster of retrogradely labeled neurons in the medial part of ventral telencephalon positioned within or adjacent to the thalamocortical pathway prior to or at the time TCAs are extending through it. The axons of these neurons extend into or through dorsal thalamus and appear to be coincident with the oppositely extending TCAs. These findings suggest that multiple cues guide TCAs along their pathway from dorsal thalamus to neocortex: TCAs may fasciculate on the axons of ventral telencephalic neurons as they extend through ventral thalamus and the medial part of ventral telencephalon, and chemorepellent and chemoattractant activities expressed by hypothalamus and ventral telencephalon, respectively, may cooperate to promote the turning of TCAs away from hypothalamus and into ventral telencephalon.

Case Studies in Couple and Family Therapy: Systemic and Cognitive Perspectives

Case Studies in Couple and Family Therapy: Systemic and Cognitive Perspectives Frank M. Dattilio (Ed.). New York: Guilford Press (www.guilford.com). 1998, 486 pp., $44.00 (hardcover). In the contemporary social sciences it is becoming well recognized that individuals actively construct the meaning of their experiences. From this postmodern perspective, distinguishing perception from interpretation becomes largely irrelevant. Causality is no longer conceived as a linear process (e.g., objective reality impinging upon subjective interpretation), but as a circular one characterized by continual feedback and interplay among the various components of complex systems. In psychotherapy, these ideas have encouraged movement away from intrapsychic models of psychopathology to those conceptualizing the individual as acting and reacting within these multiple dynamic systems. The greatest elaboration of the systems perspective has occurred in the realm of couple and family therapy, where therapists have harnessed the power of these assumptions to develop creative and powerful clinical interventions. For many cognitive-behavioral therapists, most of whom were raised on assumptions of linear causality (e.g., behavioral contingencies, cognitive distortions leading to maladaptive responses) and logical positivism (e.g., examination of objective evidence to refute distorted thoughts), the systems perspective can seem somewhat alien. On the other hand, systemic therapists may be unfamiliar with some of the directive and empirically validated therapeutic tools which are second nature to cognitive-behavioral therapists. Fortunately for practitioners of both perspectives, there now exists the informative and accessible Case Studies in Couple and Family Therapy: Systemic and Cognitive Perspectives, edited by Frank Dattilio. This volume features contributions by leading clinicians representing diverse perspectives on the treatment of couples and families, including such recognizable names as Salvador Minuchin, Norman Epstein, Donald Baucom, James Keim, David Keith, Michael Hoyt, Luciano L'Abate, Karl Tomm, and Fred Sander. Together, Dattilio and these authors have thoughtfully chosen cases that illustrate areas of intersection between the cognitive-behavioral and systemic perspectives, highlighting the possibilities for fruitful cross-pollination between the models. This is consonant with Dattilio's stated intent to facilitate theoretical integration across approaches. The case study approach is an especially congenial method of accomplishing this task. By deemphasizing theory and presenting what couple and family therapists actually do in sessions, the reader gains a wealth of compelling and useful techniques to add to his or her therapeutic arsenal. Moreover, the authors endeavor to explain how specific interventions arise from seasoned clinical intuition. Thus, the reader also is treated to (and may be somewhat awed by) the true artistry and boldness of these clinicians. What distinguishes this book from other volumes on couple and family therapy is the ongoing dialogue between the editor, representing cognitive-behavioral therapy, and the authors representing alternative theoretical perspectives. Throughout each chapter, Dattilio raises thoughtful questions, draws comparisons to a standard cognitive-behavioral approach, and provides a rationale for alternative interventions. These editorial comments appear italicized and indented within the body of each chapter's text, allowing the reader to consider alternative interventions at key decision points in the case. At the end of each chapter the authors are given an opportunity to respond to Dattilio's comments. To the credit of both the chapter authors and editor, these exchanges remain civil and constructive even where irreconcilable differences occur. This dialogic approach permits the reader to reflect on the comparative advantages and, in many cases, the compatibility, of cognitive-behavioral and systemic approaches and to consider the value of technical integration. …

The Seamless Web and Communications Equity: The Shaping of a Community Network

Drawing on field data gathered from 1994 to 1996, this article considers tensions in the development of community networks and highlights the decisions that shape particular types of networks. Four key decision points include interface choice, content, interaction, and outreach. Discourse about decision making is often dichotomized around civic and consumer social currents. Civic currents demand text-only interfaces, exclusively non- profit content, full electronic interaction capabilities for everyone, and deep outreach efforts. In contrast, consumer currents push graphical interfaces, the inclusion of profit-making content, limited interaction options, and meso to shallow outreach. While considering the influences of these currents, the article problematizes the dichotomy and considers more specific social influences on decision making. It also suggests specific network decisions that may contribute to greater communications equity.

An algorithm for otoplasty

A finesse otoplasty demands both artistry and effective surgical decision making. To this end, an algorithm outlining the key decision points in the planning and execution of the otoplasty procedure is proposed. The fundamental tenants of prominent ear reduction are outlined, and accessory techniques for manipulating the prominent lobule, repositioning the helical tail, and helical rim are described. The decision tree provides a quick reference tool, and more detailed descriptions of each step are furnished within the body of the text in rapidly accessible subsections.