临床试验进展: 适应性设计及透明性

临床试验中的适应性设计是根据累积信息来修正试验的一种设计方法,旨在使临床试验和临床开发计划效率更高,并为患者提供更加有效的治疗。此外,因信息隐匿造成试验失败和患者死亡,从而导致公众对医药行业的信任度下降,故关于公开临床数据的观点已开始朝着提升透明度方向调整。介绍3 类适应性设计方法的特点和应用,以及国外药政部门和制药企业对提高临床试验透明性的举措。     

Adaptive Learning Networks: Developing Resource Management Knowledge through Social Learning Forums

The purpose of this paper is to explore adaptive learning networks as a contemporary means by which new resource management knowledge can develop through social learning forums. The paper draws upon recent discussions within two disparate literatures on indigenous knowledge and network theory and is grounded in fieldwork with two Anishinaabe First Nations in northwestern Ontario. The paper has three objectives. First, problematize the principle of representation as a basic way of including the knowledge of indigenous peoples within natural resource and environmental management. Second, utilize network theory as a way to weave together adaptive learning by individuals into a cross-cultural social learning process. Finally, propose an adaptive natural resources and environmental framework that brings together, through a social learning process, the different ways individuals, indigenous peoples and resource managers, perceive environmental change.     

Adaptive seamless clinical trials using early outcomes for treatment or subgroup selection: Methods,simulation model and their implementation in R

Adaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, for example, in terms of sample size and/or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in the form of extensive simulation studies, than conventional approaches. Here, we present a framework for adaptive treatment and subgroup selection using the same notation, which links the somewhat disparate literature on treatment selection on one side and on subgroup selection on the other. Furthermore, we introduce a flexible and efficient simulation model that serves both designs. As primary endpoints often take a long time to observe, interim analyses are frequently informed by early outcomes. Therefore, all methods presented accommodate interim analyses informed by either the primary outcome or an early outcome. The R package asd , previously developed to simulate designs with treatment selection, was extended to include subgroup selection (so-called adaptive enrichment designs). Here, we describe the functionality of the R package asd and use it to present some worked-up examples motivated by clinical trials in chronic obstructive pulmonary disease and oncology. The examples both illustrate various features of the R package and provide insights into the operating characteristics of adaptive seamless studies.     

Trust-building, Knowledge Generation and Organizational Innovations: The Role of a Bridging Organization for Adaptive Comanagement of a Wetland Landscape around Kristianstad, Sweden

The literature on ecosystem management and assessment is increasingly focusing on social capacity to enhance ecosystem resilience. Organizational flexibility, participatory approaches to learning, and knowledge generation for responding adequately to environmental change have been highlighted but not critically assessed. The small, flexible municipal organization, Ecomuseum Kristianstads Vattenrike (EKV) in southern Sweden, has identified win-win situations and gained broad support and legitimacy for ecosystem management among a diversity of actors in the region. Navigating the existing legal-political framework, EKV has built a loose social network of local stewards and key persons from organizations at municipal and higher societal levels. As a ‘bridging organization’, EKV has created arenas for trust-building, knowledge generation, collaborative learning, preference formation, and conflicts solving among actors in relation to specific environmental issues. Ad hoc projects are developed as issues arise by mobilizing individuals from the social network. Our results suggest that the EKV approach to adaptive comanagement has enhanced the social capacity to respond to unpredictable change and developed a trajectory towards resilience of a desirable social-ecological system.

Ethical Considerations for Outcome‐adaptive Trial Designs: A Clinical Researcher's Perspective

In a typical comparative clinical trial the randomization scheme is fixed at the beginning of the study, and maintained throughout the course of the trial. A number of researchers have championed a randomized trial design referred to as ‘outcome‐adaptive randomization.’ In this type of trial, the likelihood of a patient being enrolled to a particular arm of the study increases or decreases as preliminary information becomes available suggesting that treatment may be superior or inferior. While the design merits of outcome‐adaptive trials have been debated, little attention has been paid to significant ethical concerns that arise in the conduct of such studies. These include loss of equipoise, lack of processes for adequate informed consent, and inequalities inherent in the research design which could lead to perceptions of injustice that may have negative implications for patients and the research enterprise. This article examines the ethical difficulties inherent in outcome‐adaptive trials.     

Teaching Industrial Ecology to Graduate Students: Experiences at the Norwegian University of Science and Technology

We reflect on our experiences in developing and teaching industrial ecology to interdisciplinary classes of M.Sc. and Ph.D. students. During a three-year period different ways of teaching a course in industrial ecology were tested. We conclude that an industrial ecology course has positive effects on the students' ability to acquire a holistic understanding of life-cycle environmental performance, a skill much in demand by industry. Such a course should be based on problem-oriented learning. We recommend the use of thematically-focused seminars with time for both lectures and workshops. We found that substantial participation by teachers from different disciplines and partners from industry and government is very effective. Such a course also facilitates a broader process of change within the university. Implementing industrial ecology in the university requires a joint effort and collaboration among various faculties and departments, where research activities, student projects, as well as regular student teaching and tutoring, must be complementary elements of a major interdisciplinary strategy. Such a strategy has been employed at the Norwegian University of Science and Technology (NTNU) since the first initiatives in this area were taken in 1993, and this has led to our present more comprehensive Industrial Ecology Programme (IndEcol).     

Adaptive evolutionary conservation: towards a unified concept for defining conservation units

Recent years have seen a debate over various methods that could objectively prioritize conservation value below the species level. Most prominent among these has been the evolutionarily significant unit (ESU). We reviewed ESU concepts with the aim of proposing a more unified concept that would reconcile opposing views. Like species concepts, conflicting ESU concepts are all essentially aiming to define the same thing: segments of species whose divergence can be measured or evaluated by putting differential emphasis on the role of evolutionary forces at varied temporal scales. Thus, differences between ESU concepts lie more in the criteria used to define the ESUs themselves rather than in their fundamental essence. We provide a context-based framework for delineating ESUs which circumvents much of this situation. Rather than embroil in a befuddled debate over an optimal criterion, the key to a solution is accepting that differing criteria will work more dynamically than others and can be used alone or in combination depending on the situation. These assertions constitute the impetus behind adaptive evolutionary conservation.     

Natural Resource Management: The Need for Interdisciplinary Collaboration

Human influence is now so pervasive that every ecosystem on Earth is being managed, whether intentionally or inadvertently. It is therefore imperative for scientists and managers to work together so that appropriate management regimes can be put in place wherever possible. However, it is not always clear what is appropriate, and the difficulties that often arise when scientists and managers work together can be even further compounded by the inclusion of lay stakeholders in the decision-making process. The expansion of interdisciplinary undergraduate and graduate programs would help both scientists and managers to deal more effectively with sociological issues and to understand how economic and demographic changes impact on natural resources. In addition, continuing education programs in these areas should be made available to established professionals to help them deal with new challenges. The concept of ecosystem services should be used to communicate the importance of various ecosystem components and processes to a broader audience. Consensus on a management regime can often be achieved through adaptive management. The process by which interdisciplinary collaboration can lead to new insights and research initiatives is exemplified by a resource management study on the island of Kosrae, Federated States of Micronesia. As a paradigm of natural resource management, microcosms like this small island community offer a unique opportunity for training and education. Received 4 October 2000; accepted 20 March 2001.     

Continuing education for cytotechnologists: the Australian experience

The development of a continuing education scheme for cytotechonologists in Australia is described. The process involved the establishment of a working party with Terms of Reference to review current practice in Australia and existing schemes in other parts of the world. The scheme developed takes the form of a continuing education diary that provides guidelines on the various forms of continuing education activity and corresponding credit points. The diary also provides for a record of activity to be kept. The scheme requires bi-annual submission of personal activity which is logged into a national database. A peer profile is provided and successful achievement is marked by the issue of a certificate of participation. The programme has achieved a 57% compliance in its first year of operation.     

Education for sustainability in higher education: a multiple-case study of three courses

Education for sustainability (EfS) in higher education is an emerging specialisation within the general field of EfS. EfS encompasses cognitive, affective and behavioural aspects, and aims at enhancing a variety of learning outcomes in these domains and reaching students from all programmes. One of the main challenges for higher education educators is to design courses in a way that will effectively promote the various learning outcomes of EfS. A central question is how sustainability should be integrated into the curriculum; which topics should be taught and which pedagogies ought to be applied to improve students’ knowledge, skills and motivation to promote sustainable living. The present study aimed to contribute to the knowledge about students’ learning outcomes yielded by different designs of EfS courses. This multiple-case study of three courses used a mixed-methods design. For each course, we identified its characteristics and analysed students’ self-reported learning outcomes. We found that: (1) a course with a higher degree of participatory learning, employing a system approach, promoted the highest and most varied learning outcomes; (2) the lecture-based course yielded the fewest learning outcomes; and (3) field trips promoted learning outcomes only when accompanied by more advanced pedagogies.     

The Linkage Clock: A Teaching Aid for Demonstrating the Segregation of Linked Genes

Playing cards dealt in pairs are used as a model of the behaviour of alleles in a gene pool, instead of using assorted beans or beads. They have the advantage of allowing sex determination to be incorporated; court cards can determine one sex, and by dominating other values produce a convenient sex ratio. Suit colour provides the simplest allele pair. Jokers can be used as rare recessive alleles (Iethals). Suits selected in advance provide unexpected allele frequencies. Other features of the pack allow open-ended discussion and more advanced work.     

Adaptive protein evolution of X-linked and autosomal genes in Drosophila: implications for faster-X hypotheses

Patterns of sex chromosome and autosome evolution can be used to elucidate the underlying genetic basis of adaptative change. Evolutionary theory predicts that X-linked genes will adapt more rapidly than autosomes if adaptation is limited by the availability of beneficial mutations and if such mutations are recessive. In Drosophila, rates of molecular divergence between species appear to be equivalent between autosomes and the X chromosome. However, molecular divergence contrasts are difficult to interpret because they reflect a composite of adaptive and nonadaptive substitutions between species. Predictions based on faster-X theory also assume that selection is equally effective on the X and autosomes; this might not be true because the effective population sizes of X-linked and autosomal genes systematically differ. Here, population genetic and divergence data from Drosophila melanogaster, Drosophila simulans, and Drosophila yakuba are used to estimate the proportion of adaptive amino acid substitutions occurring in the D. melanogaster lineage. After gene composition and effective population size differences between chromosomes are controlled, X-linked and autosomal genes are shown to have equivalent rates of adaptive divergence with approximately 30% of amino acid substitutions driven by positive selection. The results suggest that adaptation is either unconstrained by a lack of beneficial genetic variation or that beneficial mutations are not recessive and are thus highly visible to natural selection whether on sex chromosomes or on autosomes.     

Digital Tools for the Preservation of the Human Fossil Heritage: Ceprano, Saccopastore, and Other Case Studies

Computed tomography is presently one of the most powerful analytical tools available to investigate anatomy and morphology in palaeontological contexts. Apart from its important scientific implications, computed tomography must also be viewed as a tool to analyse the conditions of preservation of fossil remains, to plan restoration processes, and to consider fossils in terms of cultural heritage. A densitometric analysis is necessary in order to check the different geological components, the presence of infiltrations within the fossil volume, as well as the extension and presence of fractures and/or weakened surfaces. Furthermore, biomedical imaging allows non-invasive procedures of reconstruction and reproduction of the original morphology of the specimens. Digital anthropology must also be considered in view of the deontological problems associated with fossil record management and with the diffusion of science.     

Maximum likelihood estimation of generalized linear models for adaptive designs: Applications and asymptotics

Due to increasing discoveries of biomarkers and observed diversity among patients, there is growing interest in personalized medicine for the purpose of increasing the well‐being of patients (ethics) and extending human life. In fact, these biomarkers and observed heterogeneity among patients are useful covariates that can be used to achieve the ethical goals of clinical trials and improving the efficiency of statistical inference. Covariate‐adjusted response‐adaptive (CARA) design was developed to use information in such covariates in randomization to maximize the well‐being of participating patients as well as increase the efficiency of statistical inference at the end of a clinical trial. In this paper, we establish conditions for consistency and asymptotic normality of maximum likelihood (ML) estimators of generalized linear models (GLM) for a general class of adaptive designs. We prove that the ML estimators are consistent and asymptotically follow a multivariate Gaussian distribution. The efficiency of the estimators and the performance of response‐adaptive (RA), CARA, and completely randomized (CR) designs are examined based on the well‐being of patients under a logit model with categorical covariates. Results from our simulation studies and application to data from a clinical trial on stroke prevention in atrial fibrillation (SPAF) show that RA designs lead to ethically desirable outcomes as well as higher statistical efficiency compared to CARA designs if there is no treatment by covariate interaction in an ideal model. CARA designs were however more ethical than RA designs when there was significant interaction.