A comparison of various estimators of a treatment difference for a multi-centre clinical trial

When a clinical trial is conducted at more than one centre it is likely that the true treatment effect will not be identical at each centre. In other words there will be some degree of treatment-by-centre interaction. A number of alternative approaches for dealing with this have been suggested in the literature. These include frequentist approaches with a fixed or random effects model for the observed data and Bayesian approaches. In the fixed effects model, there are two common competing estimators of the treatment difference, based on weighted or unweighted estimates from individual centres. Which one of these should be used is the subject of some controversy and we do not intend to take a particular methodological position in this paper. Our intention is to provide some insight into the relative merits of the indicated range of possible estimators of the treatment effect. For the fixed effects model, we also look at the merits of using a preliminary test for interaction assuming a 10 per cent significance level for the test. In order to make comparisons we have simulated a 'typical' trial which compares an active drug with a placebo in the treatment of hypertension, using systolic blood pressure as the primary variable. As well as allowing the treatment effect to vary between centres, we have concentrated on the particular case where one centre is out of line with the others in terms of its true treatment difference. The various estimators that result from the different approaches are compared in terms of mean squared error and power to reject the null hypothesis of no treatment difference. Overall, the approach that uses the fixed effects weighted estimator of overall treatment difference is recommended as one that has much to offer.     

Evaluation of the European Spine Phantom in a multi-centre clinical trial

Transurethral resection of the prostate is the most common method of relieving urinary outflow obstruction secondary to prostatic enlargement. However, this procedure can be responsible for various complications, including irrigant-fluid absorption and blood loss, both of which are strongly dependent on operation duration time. To reduce the latter, a new resection device has been designed for transurethral prostatectomy. The device basically consists of a rotating cutting loop controlled externally, with three degrees of freedom, to fit the adenoma shape. Its performance is assessed in vitro by drilling conical and semi-ellipsoidal cavities in agar gel models. The mean difference between the calculated and obtained cavity volumes is 3% (SD = 0.9%). The volume cutting rate, found to be independent of the type of cavity drilled, is equal to 2.9 +/- 0.3 cm3 min-1. The advantages of this motorised resection device prototype are reduction in operation duration and accuracy of the resected volume. In vivo resection of a 20 cm3 adenoma in less than 15 min can be expected.     

A Bayesian model for implicit effects in perceptual identification.

Retrieving effectively from memory (REM; R. M. Shiffrin & M. Steyvers, 1997), an episodic model of memory, is extended to implicit memory phenomena, namely the perceptual identification studies reported in R. Ratcliff and G. McKoon (1997). In those studies, the influence of prior study was greatest when words were presented most briefly and when forced-choice targets and foils were most similar. R. Ratcliff and G. McKoon use these data to argue against models in which prior study changes a word's representation. A model in which prior study changes a word's representation by adding context information is fit to their data; at test, the model uses a Bayesian decision process to compare the perceptual and context features associated with the test flash to stored traces. The effects of prior study are due to matching extra context information and are larger when alternatives share many features, thereby reducing noise that attenuates these effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A randomized controlled trial of the effects of group psychological therapy on survival in women with metastatic breast cancer

In order to test the effect of a psychological intervention on survival from cancer, 66 women with metastatic breast cancer, all receiving standard medical care, were randomly assigned into two groups; one group (n = 30) attended the psychological intervention, consisting of 35 weekly, 2 h sessions of supportive plus cognitive behavioral therapy; the control group (n = 36) received only a home study cognitive behavioral package. No significant difference was found in survival post-randomization between the groups as assessed by a log rank test 5 years after the commencement of the study. As expected, several prognostic factors were significant predictors of survival: metastatic site, hormonal receptor status, and chemotherapy prior to randomization. While many personal and demographic variables did not influence survival, there was a significant effect of self-reported exercise (possibly due to better health). A small subgroup of intervention subjects who attended outside support groups also survived significantly longer than those who did not. The strengths and limitations of the present study are discussed, and the results contrasted with those of a well known study by Spiegel et al. (Spiegel, D., Bloom, J.R., Kraemer, H.C. and Gottheil, E. (1989) Lancet ii, 888-891). We propose that a different experimental design (correlative) may be needed to show any effect of self-help behaviors and psychological attributes in a small minority of patients.     

Validation of a model predicting enrollment status in a chemoprevention trial for breast cancer

A simple, rapid, and sensitive method which allows us to simultaneously determine bromvalerylurea (BVU) and its three metabolites (3-methylbutyrylurea [MVU], alpha-(cystein-S-yl)isovalerylurea [CVU], and alpha-(N-acetylcystein-S-yl)isovalerylurea [AcCVU]) was investigated by frit-fast atom bombardment liquid chromatography-mass spectrometry (frit-FAB LC-MS). The LC-MS analysis was performed after the solid-phase extraction from tissue and urine samples with a Sep-Pak C18 cartridge. Tissue homogenates and urine were adjusted to pH 4.0 and applied to the cartridges. The retained BVU and its metabolites were eluted from the cartridge with 2 mL of acetonitrile/10 mM ammonium acetate buffer (pH 3.5, 50:50, v/v). The eluate was analyzed by LC-MS, which employs a semimicro type L-column ODS column. The proposed conditions are as follows: mobile phase A, 0.4% glycerol in acetonitrile/10 mM ammonium acetate buffer (pH 3.5) (5:95, v/v); mobile phase B, 0.4% glycerol in acetonitrile; elution mode, linear gradient, 100% A (5 min) to 100% B in 15 min; flow rate, 0.2 mL/min; split ratio, 1:40. Extraction recoveries of BVU and its metabolites were 91.90-97.79% from the spiked liver homogenate and 89.68-96.13% from the spiked urine. The detection limits ranged from 10 to 25 ng/g in selected ion monitoring mode.     

A Bayesian model for growth curve analysis

An experiment involves K subjects where for subject i, ni, values yi1, yi2, ..., y(ini) of a random variable Y are observed at times ti1 ti2, ..., t(ini). Assume that yij = F(tij) +eij where eij are independently and identically distributed (i.i.d.) N(0, sigma2). We consider the estimation of the function F and the testing of the homogeneity hypothesis that, for [formula, see text] does not depend on t. The function F(i,t) is modelled as a Gaussian process which seeks to quantify the notions that for each i, F(i, t) is a slowly changing function of t and that for i is not equal to j, F(i, t), and F(j, T) are in some sense similar. We propose to estimate F (i, t) by its posterior mean given all of the data. This Bayes estimate is shown to be equivalent to a particular form of penalised likelihood estimation. We consider data-based methods for setting the parameters of the Gaussian process prior, develop a test of the homogeneity hypothesis, report the results of a Monte Carlo study illustrating the effectiveness of the proposed methodology, and apply the methods to a study of variations in temperature and blood pressure over the course of the menstrual cycle.     

Megestrol acetate for anorexia in patients with far-advanced cancer: a double-blind controlled clinical trial

The aim of this study was to evaluate a low-dose regimen of megestrol acetate (MA; 320 mg/day) on appetite in advanced cancer patients. Out-patients with far-advanced non-hormone responsive tumours and loss of appetite were randomised in a phase III trial, with two consecutive phases: a 14-day double-blind placebo controlled phase (phase A) and a 76-day open phase (phase B). During phase A, patients were treated with MA, two 160 mg tablets/day, or placebo. In phase B, the MA dose was titrated to clinical response in both groups. Appetite, food intake, body weight, performance status, mood and quality of life were evaluated with standardised measures; patients' global judgement about treatment efficacy was also requested. Of 42 patients entering the study, 33 (17 MA and 16 placebo) were evaluable for efficacy. The appetite score improved significantly with MA after 7 days (P = 0.0023), and this effect was still significant at 14 days (P = 0.0064). Patients judged the treatment with MA effective in 88.2% of cases (14th day), whilst placebo was considered effective by 25% (P = 0.0003). None of the other measures showed significant changes during treatment. The remarkable effect on appetite evident after 7 days, without serious side-effects, shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease.     

A clinical nude mouse metastatic model for highly malignant human pancreatic cancer

Pancreatic cancer is a highly aggressive and treatment-refractory cancer. A clinically-relevant animal model is necessary to develop therapy for metastatic pancreatic cancer. In this study we evaluated the efficacy of mitomycin C (MMC) and 5-FU against the human pancreatic adenocarcinoma cell line PAN-12 in an orthotopic human metastatic pancreatic cancer nude mice model. The model is constructed by surgical orthotopic implantation (SOI) of histologically intact tumor tissue in the tail portion of the pancreas near the spleen. PAN-12 grew very aggressively in the control group of nude mice with extensive local invasion and distant metastasis to various organs with a propensity for the lung but to other organs as well, including the liver, kidney and regional and distant lymph nodes. In a striking effect none of the mice in the MMC-treated group developed tumor. Although mice in the 5-FU treated group survived statistically significantly longer than those in the untreated control, the overall incidence of metastasis in these mice was equivalent to those in the control. However no liver or kidney metastases were found in the 5-FU treated animals perhaps accounting in part for their longer survival. This "clinical" nude mouse model of highly metastatic pancreatic cancer can now be used to discover new effective agents for this disease.     

A clinical trial of the INTERPLAK powered toothbrush in a geriatric population

This study was conducted to test the effectiveness of the counter-rotational powered toothbrush in a nursing home environment. A group of 60 nursing home patients were selected; each was assigned to a specific trained toothbrusher. Participants were divided into two groups stratified by gingival inflammation in a crossover-design clinical trial. Each individual used the powered brush for one 4-week period, and a manual or conventional brush for another 4-week period. A suitable period of nonintervention separated the two 4-week periods of intervention to allow plaque and gingival scores to revert to baseline. The participants were evaluated for plaque and gingivitis before and after each brushing period. The experimental brush reduced both plaque and gingivitis more effectively than the conventional brush. The mean reduction in plaque scores was 1.44 for the conventional brush, 1.92 for the powered brush (Quigley-Hein Plaque Index). The mean reduction in gingival inflammation scores was 0.47 for the conventional brush, and 0.77 for the experimental brush (L?e and Silness Gingival Index). Participants perceived the counter-rotational powered brush to be more effective, and at the exit interview overwhelmingly preferred to keep it rather than the conventional brush.     

Accuracy of clinical prediction of survival for terminally ill cancer patients

Accurate estimation of survival is vital for effective palliative care. To verify the value of clinical prediction of survival (CPS), a prospective study was performed on 150 terminally ill cancer patients. The CPS was highly correlated with actual survival (AS), but the accuracy was not significantly superior to the prediction by performance status alone. Serious pessimistic error, defined as AS was at least 28 days and twice as long as CPS, was recognized in 13%, while serious optimistic error, defined as AS was less than 28 days and half as long as CPS, in 15%. The frequency of serious error was not significantly different by physicians' experiences, patients' age, sex, primary disease, and metastatic locations, but was significantly higher in cases with better performance status. Also, unexpected changes resulting in death were experienced in 42% of another 186 cases. The main underlying causes were pneumonia, bleeding, heart failure, intestinal perforation, cerebrovascular disease, hepatic/renal failure, hypoglycemia, sepsis and electrolyte imbalance. Clinical prediction was not sufficiently reliable and must be further improved.     

Mapping the domain of expressivity: Multimethod evidence for a hierarchical model.

Increased interest in emotional expressivity has led to a proliferation of conceptions and measures. It is unclear, however, whether they all refer to the same construct and whether the domain of emotional expressivity is best conceptualized as unidimensional or multifaceted. Study 1 examined 6 common expressivity questionnaires, yielding 5 factors: Expressive Confidence, Positive Expressivity, Negative Expressivity, Impulse Intensity, and Masking. To develop a nomological network for these factors, the factors were related to broader personality taxonomies and their differential relations to sex and ethnicity were tested. Study 2 provided further evidence of discriminant validity in relation to (a) typical emotion expression in peer relationships, (b ) ability to pose emotions in the laboratory (c) likability, and (d) regulation of emotion and mood. These findings support a hierarchical model of individual differences in emotional expressivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Summary measures and statistics for comparison of quality of life in a clinical trial of cancer therapy

Assessment of health related quality of life (QOL) has become an important endpoint in many clinical trials of cancer therapy. Most of these studies entail multiple QOL scales that are assessed repeatedly over time. As a result, the problem of multiple comparisons is a primary analytic challenge with these trials. The use of summary measures and statistics both reduces the number of hypotheses tested and facilitates the interpretation of trial results where the primary question is 'Does the overall QOL differ between treatment arms?' I present two classes of summary measures that are sensitive to consistent trends in the same direction across multiple assessment times or multiple QOL scales. Missing data strongly influences the choice between the two classes, where one class handles missing data on an individual basis, while the other class uses model-based strategies. I present the results from a clinical trial of adjuvant therapy for breast cancer that use summary measures with a focus on the practical issues that affect these analysis strategies, such as missing data and integration of QOL with efficacy endpoints such as survival.     

Novel bifunctional anthracycline and nitrosourea chemotherapy for human bladder cancer: analysis in a preclinical survival model

A hybrid drug [N-2-chloroethylnitrosoureidodaunorubicin (AD312)] that combines structural and functional features of both anthracyclines and nitrosoureas was evaluated in a preclinical survival model of human bladder cancer. To measure the therapeutic activity of AD312, UCRU-BL13 transitional cell carcinoma cells were grown as xenografts in nude mice, and tumor growth rates were compared after i.v. administration of the drug at three dose levels. AD312 treatment at 45 and 60 mg/kg achieved 7-10-fold inhibition of tumor growth and increased host survival by 156 and 249%, respectively. Doses of 60 mg/kg showed optimal therapeutic efficacy, with sustained tumor growth inhibition, an over 2-fold increase in life span, and 40% of mice tumor free ("cured") at 120 days. Tumors were unresponsive to maximum tolerated doses of doxorubicin, a standard anthracycline used as a single agent and in combination therapies for bladder cancer. 1,3-Bis-[2-chloroethyl]-1-nitrosourea was used as a control for the apparently enhanced response of human tumors in murine hosts to nitrosoureas. 1, 3-Bis-[2-chloroethyl]-1-nitrosourea administered in three injections of 20 mg/kg did not cure mice but temporarily inhibited tumor growth by 70% and prolonged survival by 55%; its activity in this model suggests that it may be included in the repertoire of alkylating agents currently used for treatment of bladder cancers. AD312 showed increased antitumor activity with less toxicity than doxorubicin, and its bifunctional properties provide the opportunity for simultaneous treatment of individual cancer cells with two cytotoxic modalities as well as treatment of heterogeneous populations typical of bladder cancers. This novel cytotoxic drug cured doxorubicin-refractory disease and should be investigated for the clinical management of bladder cancer.     

A confidence-credibility model of expert witness persuasion: Mediating effects and implications for trial consultation.

Trial consultation is a quickly growing domain of professional practice for psychologists. Preparing expert witnesses to testify is just one prime example of practice options for consultants. A wealth of evidence shows that developing expert confidence and credibility are important goals for witness training. However, research has yet to articulate a list of testimony delivery skills needed to bolster perceptions of credibility and agreement with the expert. The present study advances expert credibility theory and trial consultation practice by empirically validating a confidence-credibility mediation model of expert witness persuasion. It is argued that this model, grounded in credibility and confidence theories, can be integrated with existing methods of witness preparation training. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Confidence intervals for median survival times under a piecewise exponential model with proportional hazards covariate effects

SECIS elements are stem-loop structures located in the 3' untranslated regions (UTRs) of eukaryotic selenoprotein mRNAs that are required for directing cotranslational selenocysteine incorporation at UGA codons. In prokaryotes, stem-loops mediating selenocysteine incorporation are located immediately downstream of the UGA selenocysteine codon, in the coding region. Previous characterization studies of the mammalian SECIS elements of type 1 deiodinase, glutathione peroxidase, and selenoprotein P showed that conserved nucleotides in the loops and unpaired bulges, and base pairing in the stems are required for SECIS function. These initial studies utilized approximately 175-230-nt segments of the 3'UTRs of the selenoprotein mRNAs. Here we define the minimal functional rat type 1 deiodinase SECIS element, a 45-nt segment, the 5' boundary of which corresponds precisely to the 5'-most critical conserved nucleotide identified previously. We also define base pairing requirements in the stem of this element. In view of the presence of SECIS elements in the open reading frames (ORFs) of bacterial selenoproteins, we examine the effects in the type 1 deiodinase of extending the ORF into the SECIS element, and find that this dramatically inhibits SECIS function. Finally, we define a minimal spacing requirement of 51-111 nt between a eukaryotic UGA selenocysteine codon and SECIS element.     

An introduction to survival analysis: Statistical methods for analysis of clinical trial data.

The randomized controlled clinical trial (RCT) is a prospective study using random assignment of subjects to treatment groups to compare the effect and value of a therapeutic intervention against a control. The RCT is the most definitive clinical research tool for evaluating the efficacy of a new therapy in human subjects. Often the outcome of interest in an RCT is the length of time until an event occurs after treatment or intervention. In this article we introduce statistical methods for evaluating differences in the patterns of time to response between two groups of subjects to determine whether one therapy is better than another. The collection of methods for analyzing such data, known as survival data, is called survival analysis. Using data from a hypothetical clinical trial for the prevention of the recurrence of depression, we illustrate two elementary methods for analyzing survival data. We also discuss generalizations of these methods to incorporate covariates and conclude with a general discussion of clinical trials of psychiatric therapies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A multivariate hierarchical model for studying psychological change within married couples.

This article illustrates new statistical methods for the study of psychological change in married couples. The design involves time-series data on each partner. The analysis combines longitudinal methods for studies of individual change with cross-sectional methods for the study of matched pairs. Each person is viewed as changing over time as a function of an individual growth curve or change function. As in previous studies of individual change, a person's trajectory depends on time-invariant personal background characteristics and time-varying changes in the environment. However, unlike typical studies of individual change, a person's changing psychological profile depends, in part, on the influence of that person's partner. These methods apply directly to other types of longitudinal studies on families (e.g., studies that use teacher and parent reports of a child's social behavior). The methodology is flexible in allowing randomly missing data, varying spacing of time points, unbalanced designs, and time-varying and time-invariant covariates. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

底吹钢包用圆孔透气砖冶金效果的水模型

采用水力学模型方法对钢包底吹氩工艺进行了实验研究,对比分析了圆孔型透气砖与狭缝式透气砖对冶炼效果的影响,并研究了圆孔透气砖的孔角和孔径对混匀时间、夹杂物去除率和渣眼面积的影响规律.结果表明:当吹气流量相同时,使用圆孔斜通透气砖时,钢包的混匀时间、夹杂物去除率和渣眼面积均优于狭缝式透气砖;相比于圆孔直通透气砖的钢包,使用圆孔斜通透气砖的钢包混匀时间更短,去除夹杂物效果佳,但渣眼面积略大;对于圆孔斜通透气砖,其孔径越小,钢包混匀时间越短,夹杂物去除率越高,渣眼面积越小.