Diet and disease

In this era of evidence based medicine information about diet and diseases is less certain than information about drugs and diseases. Drug treatment is less complex. Dietary change can't usually be incorporated in a double blind trial. There is much more funding for pharmaceutical trials than for dietary trials. The following notes concentrate on newer, developing concepts.     

In search of power and significance: issues in the design and analysis of stochastic cost-effectiveness studies in health care

Application of techniques such as cost-effectiveness analysis (CEA) is growing rapidly in health care. There are two general approaches to analysis: deterministic models based upon assumptions and secondary analysis of retrospective data, and prospective stochastic analyses in which the design of a clinical experiment such as randomised controlled trial is adapted to collect patient-specific data on costs and effects. An important methodological difference between these two approaches is in the quantification and analysis of uncertainty. Whereas the traditional CEA model utilizes sensitivity analysis, the mean-variance data on costs and effects from a prospective trial presents the opportunity to analyze cost-effectiveness using conventional inferential statistical methods. In this study we explored some of the implications of moving economic appraisal away from deterministic models and toward the experimental paradigm. Our specific focus was on the feasibility and desirability of constructing statistical tests of economic hypotheses and estimation of cost-effectiveness ratios with associated 95% confidence intervals. We show how relevant variances can be estimated for this task and discuss the implications for the design and analysis of prospective economic studies.     

An ergonomic evaluation of a patient handling device: the elevate and transfer vehicle

This study evaluated a Patient Handling Device (PHD) called the Elevate and Transfer Vehicle (ETV). The ETV works on the principle of leverage to transfer a patient from one seated position to another. Three types of product evaluation were used: expert appraisal; user trials; and performance tests. Expert appraisal was conducted by a panel of 11 people including an ergonomist, an industrial designer, two engineers, including one employed as an academic in a School of Mechanical, Manufacturing and Medical Engineering, and seven health professionals. The experts evaluated the ETV using a checklist and group discussions. They generally agreed that the advantages of the ETV tested were it's simplicity, the convenient position to adjust clothing for toileting and the need for only one carer. They noted comfort, security of straps, centre of gravity and manoeuvrability as the main areas for improvement. User trials consisted of nine male and nine female volunteer users assigned to carer/patient pairs. Following a training period, each user subjectively evaluated the ETV by structured interview. User trial results indicated ease of use, prevention of back injuries in carers and minimal body contact were advantages of the ETV. The main problems with using the ETV appeared to be the inadequate 'prop' and straps, the 'jolt' and lack of dignity for the patient. Several critical performance tests were conducted to determine compliance to Australian Standards for design. Areas of non-compliance included strength of frame and static stability. The findings suggest that most of the identified problems of the ETV could be overcome with minor design improvements. The general consensus of participants was to keep the design simple, maintain fast transfers and maintain the position of the patient to enable ease of clothing adjustment for toileting.     

A method for the continuous purification of proteins by affinity adsorption

The Food and Drug Administration (FDA) must manage the delicate balance between speed and safety in the evaluation and approval of new drugs. To explore how these competing obligations might be formalized with respect to the AIDS epidemic, we present a simple decision-theoretic optimization model of the clinical trials process against a backdrop of HIV transmission. Our framework sheds light on such issues as the economic consequences of decisions, the potential savings of a new therapy, the costs to society of delay, the value of better information, and how and when to undertake a clinical trial. We believe that this article represents a first effort to unravel the tangled web of epidemiological, economic, and statistical considerations that plague this policy issue.     

Meta-analysis of multiple outcomes by regression with random effects

Earlier work showed how to perform fixed-effects meta-analysis of studies or trials when each provides results on more than one outcome per patient and these multiple outcomes are correlated. That fixed-effects generalized-least-squares approach analyzes the multiple outcomes jointly within a single model, and it can include covariates, such as duration of therapy or quality of trial, that may explain observed heterogeneity of results among the trials. Sometimes the covariates explain all the heterogeneity, and the fixed-effects regression model is appropriate. However, unexplained heterogeneity may often remain, even after taking into account known or suspected covariates. Because fixed-effects models do not make allowance for this remaining unexplained heterogeneity, the potential exists for bias in estimated coefficients, standard errors and p-values. We propose two random-effects approaches for the regression meta-analysis of multiple correlated outcomes. We compare their use with fixed-effects models and with separate-outcomes models in a meta-analysis of periodontal clinical trials. A simulation study shows the advantages of the random-effects approach. These methods also facilitate meta-analysis of trials that compare more than two treatments.     

A case for Bayesianism in clinical trials

This paper describes a Bayesian approach to the design and analysis of clinical trials, and compares it with the frequentist approach. Both approaches address learning under uncertainty. But they are different in a variety of ways. The Bayesian approach is more flexible. For example, accumulating data from a clinical trial can be used to update Bayesian measures, independent of the design of the trial. Frequentist measures are tied to the design, and interim analyses must be planned for frequentist measures to have meaning. Its flexibility makes the Bayesian approach ideal for analysing data from clinical trials. In carrying out a Bayesian analysis for inferring treatment effect, information from the clinical trial and other sources can be combined and used explicitly in drawing conclusions. Bayesians and frequentists address making decisions very differently. For example, when choosing or modifying the design of a clinical trial, Bayesians use all available information, including that which comes from the trial itself. The ability to calculate predictive probabilities for future observations is a distinct advantage of the Bayesian approach to designing clinical trials and other decisions. An important difference between Bayesian and frequentist thinking is the role of randomization.     

Decision making during a phase III randomized controlled trial

Experiments such as clinical trials should be carried out with specific objectives. For example, in a trial designed to prevent disease, specific considerations should be made concerning the impact of the trial on the health of the target population, including the participants in the trial. These objectives should be assessed continually in light of data accumulating from the trial. Accumulating evidence should be judged in the context of changing circumstances external to the trial, and the trial's design possibly modified. An important type of modification is stopping the trial. This is a sequential decision problem that can be addressed using a Bayesian approach and the methods of dynamic programming. As an example we consider a vaccine trial for the prevention of haemophilus influenzae type b. The objective we consider is minimizing the number of cases of this disease in a Native American population over a specified horizon. We assess the prior probability distribution of vaccine efficacy. We also assess the probability of regulatory approval for widespread use of the vaccine, depending on the data presented to the regulatory officials. In deciding whether to continue the trial we weigh the impact of the possible future results by their (predictive) probabilities. We address the sensitivity of the optimal stopping policy to the prior probability distribution, to the assessed probability of regulatory approval, and to the horizon.     

Suppression of synaptogenesis by epileptiform discharges in hippocampal slice culture

Epidemiological and laboratory studies provide preliminary evidence that a compound may prevent certain types of clinical cancer. The final proof for practical application demands two controlled trials with similar, decisive results. Controlled chemoprevention trials on clinical cancer are large, time-consuming and expensive, whereas studies on cancer surrogates are smaller but less reliable. Rational trial design often lacks sufficient information about the sensitive period and the time from that point to clinically detectable cancer. The correct dose of chemopreventive agent and an expected preventive fraction of cancer are also often based on informed guesswork. Long trials call for special arrangements to guarantee the staying will of the participants and key research personnel. Although large chemoprevention trials are currently being carried out without any certainty of successful outcome, the situation is not so different from the early days of chemoprevention trials for cardiovascular diseases. Cancer trials will be conducted based on the 'learning-by-doing' approach, and in the more distant future based on research designed to provide information for trial needs.     

Investigating psychosocial aspects of participation in early anti-cancer drug trials: towards a choice of methodology

This paper presents the methodological approach and research methods chosen to explore psychosocial aspects of participation in early anti-cancer drug trials from the perspective of those actually involved. The paper describes how an appropriate methodology, or principles of reasoning behind the choice of research methods, emerged. The choice of methodology was based on three elements: first, an understanding of the competing philosophies about how research can be approached and conducted; second, the author's view of the subject area; and third, a consideration of previous research approaches which have investigated psychosocial aspects of cancer clinical trials. A qualitative methodology situated within an interpretative paradigm was eventually chosen as the most appropriate means of exploring trial participants' experiences and the aim and objectives of the research were developed within this methodological framework.     

Modelling and design of cross-over trials

There are many diseases and conditions that can be studied using a cross-over clinical trial, where the subjects receive sequences of treatments. The treatments are then compared using the repeated measurements taken 'within' subjects. The actual plan or design of the trial is usually obtained by consulting a published table of designs or by applying relatively simple rules such as using all possible permutations of the treatments. However, there is a danger is this approach because the model assumed for the data when the tables or rules were constructed may not be appropriate for the new trial being planned. Also, there may be restrictions in the new trial on the number of treatment sequences that can be used or on the number of periods of treatment particular subjects can be given. Such restrictions may mean that a published design of the ideal size cannot be found unless compromises are made. A better approach is to make the design satisfy the objectives of the trial rather than vice versa. In this paper we describe an approach to constructing such tailor-made designs which we hope will lead to ill-fitting 'off the peg' designs being a thing of the past. We use a computer algorithm to search for optimal designs and illustrate it using a number of examples. The criterion of optimality used in this paper is A-optimality but our approach is not restricted to one particular criterion. The model used in the search for the optimal design is chosen to suit the nature of the trial at hand and as an example a variety of models for three treatments are considered. We also illustrate the construction of designs for the comparison of two active treatments and a placebo where it can be assumed that the carry-over effects of the active treatments are similar. Finally, we illustrate an augmentation of a design that could arise when the objectives of a trial change.     

Employee perceptions of performance appraisal fairness in two organizations.

Studied the characteristics comprising the appraisal process from the employees' perspective and how those characteristics related to employee perceptions of performance appraisal fairness. Based upon factor analysis of survey data from a total of 397 management and professional employees in 2 large Canadian organizations, 6 characteristics were found to comprise the appraisal process: appraiser's knowledge of the employee's job and performance, opportunity for employee participation, establishment of specific and relevant job goals, discussion of employee development goals, discussion of company and department goals, and feedback on results. The relative importance of these characteristics to overall appraisal fairness ratings was different in the 2 companies. The favorableness of the most recent appraisal was associated with the employee's belief in the overall fairness of the appraisal process in both companies. (French abstract) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Characteristics of protrusive and lateral excursions of the mandible in children with the primary dentition

Collection of patient-centred health status is a method for quantifying patient outcome in the context of clinical trials for the treatment of coronary artery disease (CAD). Traditional clinical trial end-points, such as morbidity and mortality, fail to adequately measure the health-related outcomes of disease states for which death is a rare occurrence. Health-related quality of life (QOL) and functional status surveys allow measurement of the general, and/or disease-specific, health-related limitations experienced by patients. Measures of patient preference, in turn, quantify the effects these health-related limitations have on the overall value patients ascribe to their current health state. Together, these outcomes measures may provide a more accurate appraisal of the benefit conferred by treatment. Currently, selection of the appropriate outcomes measures and methodological approaches for a clinical trial is complicated by the lack of consensus on a single quality of life measure for use with patients with (CAD). This article outlines the use of QOL measures in anti-anginal trials done to date and summarises the approaches currently available for assessing QOL, including the differences between psychometric and preference-based techniques, and general and disease-specific health measures. In conclusion, a framework is provided for selecting the appropriate instruments and methodology in the context of the clinical trial.     

The population risk as an explanatory variable in research synthesis of clinical trials

The population risk, for example the control group mortality rate, is an aggregate measurement of many important attributes of a clinical trial, such as the general health of the patients treated and the experience of the staff performing the trial. Plotting measurements of the population risk against the treatment effect estimates for a group of clinical trials may reveal an apparent association, suggesting that differences in the population risk might explain heterogeneity in the results of clinical trials. In this paper we consider using estimates of population risk to explain treatment effect heterogeneity, and show that using these estimates as fixed covariates will result in bias. This bias depends on the treatment effect and population risk definitions chosen, and the magnitude of measurement errors. To account for the effect of measurement error, we represent clinical trials in a bivariate two-level hierarchical model, and show how to estimate the parameters of the model by both maximum likelihood and Bayes procedures. We use two examples to demonstrate the method.     

Multiple-outcome meta-analysis of clinical trials

When several clinical trials report multiple outcomes, meta-analyses ordinarily analyse each outcome separately. Instead, by applying generalized-least-squares (GLS) regression, Raudenbush et al. showed how to analyse the multiple outcomes jointly in a single model. A variant of their GLS approach, discussed here, can incorporate correlations among the outcomes within treatment groups and thus provide more accurate estimates. Also, it facilitates adjustment for covariates. In our approach, each study need not report all outcomes nor evaluate all treatments. For example, a meta-analysis may evaluate two or more treatments (one 'treatment' may be a control) and include all randomized controlled trials that report on any subset (of one or more) of the treatments of interest. The analysis omits other treatments that these trials evaluated but that are not of interest to the meta-analyst. In the proposed fixed-effects GLS regression model, study-level and treatment-arm-level covariates may be predictors of one or more of the outcomes. An analysis of rheumatoid arthritis data from trials of second-line drug treatments (used after initial standard therapies prove unsatisfactory for a patient) motivates and applies the method. Data from 44 randomized controlled trials were used to evaluate the effectiveness of injectable gold and auranofin on the three outcomes tender joint count, grip strength, and erythrocyte sedimentation rate. The covariates in the regression model were quality and duration of trial and baseline measures of the patients' disease severity and disease activity in each trial. The meta-analysis found that gold was significantly more effective than auranofin on all three treatment outcomes. For all estimated coefficients, the multiple-outcomes model produced moderate changes in their values and slightly smaller standard errors, to the three separate outcome models.     

Traditional and alternative research designs and methods in clinical pediatric psychopharmacology

OBJECTIVE: To review both traditional and alternative research designs and methods in pediatric psychopharmacology. METHOD: Study designs used in clinical trials in psychiatry were selected for review with the special considerations of pediatric psychopharmacological trials in mind. Where possible, a reference to a specific published trial in pediatric psychopharmacology was provided for each design. RESULTS: It appears that pediatric psychopharmacology trials require a relatively greater flexibility in design to avoid significant study biases. Alternative research designs may be preferable to the traditional approaches, particularly when the use of the latter may raise important issues of feasibility. CONCLUSIONS: Evolution of a clinical research hypothesis to a study protocol in pediatric psychopharmacology is a manageable task if one keeps in mind essential elements such as selection of study design, population, sample size, treatment duration, and efficacy assessments.     

Sequential Compatibility Effects and Cognitive Control: Does Conflict Really Matter?

Although it is widely accepted that control mechanisms are necessary for human behavior to be adapted, very little is known about how such mechanisms are recruited. A suggestion to fill the gap was put forward by M. M. Botvinick, T. S. Braver, C. S. Carter, D. M. Barch, and J. D. Cohen (2001), who proposed the conflict-loop theory. This theory has been successful in accounting for the reduction of compatibility effects after an incompatible trial: The level of conflict being, on average, higher during an incompatible trial, more control occurs after such a trial. The authors have tested this prediction by sorting the trials on the basis of amount of conflict (quantified by the electromyographic activity) they presented. A reduction of the compatibility effect was observed after incompatible trials, but it was independent of the level of conflict on previous trials, suggesting that the conflict does not trigger changes in executive control. Consequences for the conflict monitoring model are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pigs in space: spatial memory and its susceptibility to interference

This study provided basic information about spatial memory in the domestic pig, Sus scrofa and examined how susceptible it is to disruption by environmental stimuli. Eight male pigs were tested individually in a foraging arena. Each day, they entered the arena to search for food randomly located in one of 10 enclosed areas (search trial). After finding and eating the food, they were removed from the arena for a retention interval, and then allowed back in to relocate the food in the same area as previously (relocation trial). Once pigs had achieved a criterion level of performance in relocation trials, 'disturbances' (e.g. isolation, novel food source, novel spatial environment) were presented during the retention interval. Disturbance days were separated by control days on which no disturbance was presented. During search trials, pigs did not use food-related cues to locate food, but appeared to use memory to search systematically and avoid revisits to empty areas. During relocation trials, they found food using fewer area visits than expected by chance, indicating that they could remember the location of food across both 10-min and 2-h retention intervals. Disturbances administered during 10-min retention intervals resulted in more relocation errors than on corresponding control days, indicating that spatial memory in pigs is susceptible to interference by relatively mild environmental stimuli, in contrast to that in rats, Rattus norvegicus and pigeons, Columba livia which appears to be highly resistant to retroactive interference even when potent stimuli are used. Analysis of error locations suggested that disturbances probably acted to increase the general area in which the pig remembered the food to be located, and so reduced accuracy of memory without eradicating it. There was no evidence that errors made during relocation trials represented sampling of areas not visited during the preceding search trial.Copyright 1997 The Association for the Study of Animal Behaviour     

Malaria therapy in the era of chloroquine resistance

Despite few efforts to develop new antimalarial compounds by the major pharmaceutical companies, some promising new therapeutics have been developed and tested clinically by small groups and companies throughout the world. Really new substances are scarce but combinations of known medicarnents have been shown to be a rational and effective approach to overcome problems with single compounds. Additionally, combination regimens are more easily authorized and accepted for treatment than completely new substances. Some examples in this respect are combinations of either atovaquone, doxycycline or clindamycin with a 'classical' antimalarial. Artemisinin, benflumetol and pyronaridine were originally developed in China and disperse currently to the rest of the world. First independent and international clinical trials gave promising results and one should bear in mind those substances for future applications. Especially artemisinin and its derivatives are of great interest because they represent, besides quinine, the only other therapeutic option for the treatment of multidrug-resistant severe malaria.     

中国海外矿业投资决策过程基本框架和方法

 矿业投资直接决定着矿业公司未来的资源配置状况,直接改变着矿业公司的生产经营内容、结构和能力。为了提高矿业投资决策的科学性,对其过程基本框架的研究显得十分必要。笔者从一个海外矿业投资实例出发,通过分析和总结,建立了包括投资环境的评价、项目价值评估等关键步骤的矿业投资决策过程基本框架,并且对应用的环境评价和实物期权方法进行了研究,矿业企业可以利用此框架作为工具辅助决策。