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In this paper we describe a decision analytic approach to doing a futility analysis of a phase II study on a drug under development. For this analysis we build a model that estimates the expected monetary value of the drug and the expected costs of development. These statistics are used to help decide whether to continue the study.
AIM: To use different analytical approaches to data from a longitudinal, quasi-experimental study evaluating caries-preventive measures in order to estimate the differences in results due to the analytical tool used. METHODS: 1,165 patients at high risk for caries underwent yearly examinations in 1996, 1997 and 1998 and randomly received one out of four tested preventive measures. Two analytical methods were used: (1) increment was calculated using the indices DMFS(a) and D(e)MFS(a), (2) incidence density was calculated for each individual using new approximal dentin lesions or dentin and enamel lesions in the numerator and the risk time for the surfaces in the denumerator. The Poisson regression with overdispersion was used for multivariate modelling of the outcomes. RESULTS: In all analyses of approximal dentine as well as dentine and enamel caries bad oral health at baseline increased the risk of new approximal dentine caries. In the incidence analysis poor oral health behaviour also increased the risk. CONCLUSION: Since the difference between the two analytical methods are small for young individuals the method of preference would be increment analysis.
This paper presents a case study involving a meta-analytic approach for an integrated summary of efficacy based upon four phase II and III clinical trials that comprised the basis for a Biologics License Application to the U.S. Food and Drug Administration for approval of becaplermin gel. There were substantial variations in observed response rates across the four studies that were of concern to regulatory agencies. Due to these variations and because there were various treatment combinations in the four trials, standard statistical methods for an integrated analysis of efficacy were problematic. A meta-analytic model that focused on the variations of concern was employed to permit a suitable integrated analysis. The resulting integrated analysis clarified response rate variability and provided accurate estimates of treatment effects based upon the four clinical trials. While this meta-analysis was viewed by neither regulators nor the sponsor as a confirmatory analysis, it was seen by both regulators and sponsor as strongly supportive of the efficacy of becaplermin gel.
Traditional Chinese medicines have attracted great interest in recent researchers as alternative antineoplastic therapies. This review focuses on analytical approaches to various aspects of the antineoplastic ingredients of traditional Chinese medicines. Emphasis will be put on the processes of biological sample extraction, separation, clean-up steps and the detection. The problems of the extraction solvent selection and different types of column chromatography are also discussed. The instruments considered are gas chromatography, capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) connected with various detectors (ultraviolet, fluorescence, electrochemistry, mass, etc.). In addition, determinations of antineoplastic herbal ingredients, including camptothecin, taxol (paclitaxel), vinblastine. vincristine, podophyllotoxin, colchicine, and their related compounds, such as irinotecan, SN-38, topotecan, 9-aminocamptothecin, docetaxel (taxotere) and etoposide, are briefly summarized. These drugs are structurally based on the herbal ingredients, and some of them are in trials for clinical use. Evaluation of potential antineoplastic herbal ingredients, such as harringtonine, berberine, emodin, genistein, berbamine, daphnoretin, and irisquinone, are currently investigated in laboratories. Other folk medicines are excluded from this paper because their antineoplastic ingredients are unknown.
We report a survey on urine drug testing within a total of 269 laboratories of the European Union. Clinical laboratories predominated over forensic laboratories (59.5% vs 28.5%). Screening without identification/quantification was the common approach used by clinical laboratories, whereas screening with identification/quantification was the approach used by almost all forensic laboratories. Screening was primarily performed by immunoassay in both types of laboratories. Gas chromatography coupled to mass spectrometry was the main analytical method used for specific identification/quantification of drugs, but other methods (including immunoassays) were also used. Cutoff values applied varied by laboratory type, country, and method used. A high percentage of laboratories did not use or report cutoff values. Overall, countries of the European Union vary significantly in regards to drugs tested, analytical approach, and screening and identification cutoff values. It is recommended to clearly state the analytical method and the cutoff values used when reporting results for drugs of abuse testing.
The quality and costs of residential services for 40 adults with severe learning disabilities and sensory impairments across four different service models were evaluated. A path analytic approach was used to calculate factors associated with four indicators of service quality: (1) assistance received by residents from staff; (2) positive contact received by residents from staff; (3) resident engagement in constructive activity; and (4) the level of physical integration of residents. The path analyses accounted for between 50 and 77% of the variance in the indicators. Factors found to be commonly associated with all four indicators included a community location, a specialized service orientation, the cognitive abilities of residents and a high level of scheduled activity. Service resources in the form of costs or staff ratios were not associated with any indicator of service quality. The findings strongly suggest an inverse system of care in that residents with greater skills receive more staff support. The implications of these and other findings for further research and service practice are discussed.
A meta-analysis of an earlier multicenter, double-blind efficacy study comparing placebo, oxaprotiline and amitriptyline was performed in order to test the survival-analytical approach in modelling the onset of improvement and response to treatment with antidepressants. The sample consisted of moderately depressed male (n = 154) and female (n = 275) patients (aged 17-73), diagnosed according to DSM-III criteria for major depression. Of these, 120 were treated with oxaprotiline, 120 with amitriptyline and 189 with placebo. Efficacy criteria were Hamilton Depression (HAMD) and Anxiety (HAMA) and Zung Self-Rating scales. Up to eight ratings over a period of 40 days were available for analysis. The results showed that the sensitivity in discriminating between groups was substantially enhanced through the inclusion of drop-outs and consideration of the effect of time to withdrawal from the study due to lack of improvement. Withdrawal from the trial due to inefficacy occurred earliest under placebo (50% within the first 8 days), whereas less than 40% dropped out within the first 12 days under active treatments. The most interesting and unexpected finding of the analysis was that the time course of improvement among responders was independent of the treatment modality, and thus identical in all three groups. Specifically, the efficacy of any of the given treatments was reflected only by the total number of responders or nonresponders. Once triggered, the time course of recovery from illness becomes identical to that of spontaneous remissions as observed, for example, under placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
The acoustic attenuation performance of perforated dissipative circular expansion chambers with inlet/outlet extensions is investigated. The eigenvalues and eigenfunctions of the sound field are analytically determined in the extended inlet/outlet circular ducts, upstream/downstream end annular dissipative chambers, and the central perforated dissipative expansion chamber. Utilizing the continuity conditions of velocity/pressure at the interfaces the transmission loss is predicted by a two-dimensional analytical approach. For a specific configuration, such predictions are compared with both experiments and a three-dimensional computational solution based on the substructure boundary element technique, showing a reasonable agreement. The analytical results for the effect of the absorbent resistivity, duct porosity, and geometryon the acoustic attenuation performance are discussed in detail.
The aim of this study was to examine the nature and organization of a range of negative self-statements in children and adolescents, using a structural equations/confirmatory factor-analytic approach. A community sample of 978 children aged 7-16 years completed a questionnaire about the frequency with which they experienced a broad range of negative automatic thoughts. The outcome of comparative modeling provided strongest support for a model in which 4 distinct cognitive factors were all related to a single higher order factor. The 4 lower order factors related to cognitions on social threat, physical threat, personal failure, and hostility. The pattern of results was consistent across age and gender. Results were consistent with assumptions of cognitive specificity models of psychopathology, on the latent structure of automatic thoughts in children and adolescents.
Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0-6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2-0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D' = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7-3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene-gene and gene-environment interactions.
Behavior analysis has much to offer the study of phenomena in the area of judgement and decision making. We review several research areas that should continue to profit from a behavior-analytic approach, including the relative merit of contingency-based and rule-governed instruction of solving algebra and analogy problems, and the role of conditioned reinforcement and the inter-trial interval in a type of Prisoner's Dilemma Game. We focus on two additional areas: (1) the study of base-rate neglect, a notorious reasoning fallacy and (2) the study of the sunk-cost effect, which characterizes ill-conceived investment decisions. In each of these two cases we review studies with humans and pigeons as subjects.
PROBLEM: Given the lack of a consistent factor structure of safety climate, this study tested the stability of a factor structure of a safety climate scale developed through an extensive literature review using confirmatory factor analytic approach and cross-validation. METHODS: A cross-sectional sample of 722 U.S. grain industry workers participated in the questionnaire survey. RESULTS: The safety climate scale developed through the generation of an item pool based on a table of specifications, subsequent scientific item reduction procedures, reviews from experts, and pilot test yielded adequate reliabilities for each dimension. Each item showed proper discriminative power based on both internal and external criteria. Criterion validity was manifested by the significant positive correlation of the scale with five criteria. Evidence of construct validity was provided by both exploratory and confirmatory factor analyses. Both calibration and validation samples supported a consistent factor structure. Management commitment and supervisor support were found to influence other dimensions of safety climate. DISCUSSION: This study provides an insight into the primary reason why previous attempts have failed to find a consistent factor structure of safety climate: No specification of the influence of management commitment and supervisor support on other dimensions of safety in their models. IMPACT ON INDUSTRY: The findings of this study provide a framework upon which accident prevention efforts can be effectively organized and underscore the importance of management commitment and supervisor support as they affect employee safety perceptions.
INTRODUCTION: Hypertension constitutes a veritable public health issue. Several classes of drugs are available for the treatment of hypertension. The objective of this meta-analytical approach was to assess the efficacy of antihypertensive drugs most commonly used in France in reducing clinical SBP and DBP. METHODS: The antihypertensive drugs selected were hydrochlorothiazide, indapamide sustained release (SR), furosemide and spironolactone for diuretics; amlodipine and lercanidipine for calcium channel antagonists; atenolol for beta-adrenoceptor antagonists (beta-blockers); enalapril and ramipril for ACE inhibitors; and candesartan cilexetil, irbesartan, losartan, and valsartan for angiotensin II receptor antagonists. The trials selected were published between 1973 and 2004, evaluated monotherapy with trial drugs as fixed-dosage or with dosage increase, and assessed blood pressure reduction between 2 and 3 months. The analysis method used was based on the calculation of the sum weighted for the trial size. RESULTS: A total of 72 trials (comprising 9094 patients) were selected and analyzed. No trial evaluating furosemide or spironolactone satisfied the inclusion criteria for this analysis. For SBP, the reduction was more marked with diuretics, calcium channel antagonists, and ACE inhibitors. Of all the drugs studied, indapamide SR gave the greatest SBP reduction (-22.2 mm Hg). Evaluated therapeutic classes had a similar magnitude of effect on DBP, i.e. reduction between -11.4 mm Hg with beta-adrenoceptor antagonists and -10.3 mm Hg with angiotensin II type 1 receptor antagonists. CONCLUSION: Indapamide SR 1.5 mg appeared to be the most effective drug for a significant reduction in SBP within 2-3 months, which is an essential element in optimizing cardiovascular prevention among hypertensive patients. The clinical application of these results should take into consideration all the limitations discussed in this analysis.
Traditional univariate comparisons of nerve conduction data against standard norms may produce conflicting estimates of the presence or absence of a diabetic neuropathy, depending upon the data obtained and the specific nerves sampled. Alternatively, a multivariate analytic approach, using discriminant functions, provides a useful single measure of the degree of neuropathy determined as a weighted combination of the available data. The weights are derived from the linear discriminant function, which maximizes statistical separation of diabetic and nondiabetic subject groups. In this study, 12 electrophysiologic attributes are used to generate a single discriminant function that clearly separates diabetic from nondiabetic subjects and is interpretable as a neuropathic index. Each individual's index of diabetic neuropathy (I) can be quantified as follows: (Formula: see text) where Ai is the original electrophysiologic attribute (i = 12), ai is the coefficient for each attribute that defines the discriminant function and C is a constant specific for that function. For the first time, the degree of diabetic neuropathy can thus be quantified for purposes of comparison and correlation with other quantifiable clinical/somatic measures of diabetes. The index allows for a higher percentage of type II diabetic patients to be classified as neuropathic than previously described and enables determination of degree of neuropathy is affected individuals by an interpolative method.
Many of the problems associated with the delivery of quality veterinary services to smallholders in Africa are attributed to the complexity of the provision of animal health care (AHC) in sub-Saharan Africa. In this region, a holistic and analytical approach is needed to determine area-specific requirements for sustainable, and thus quality, AHC. This study examines three components of the animal health care system in sub-Saharan Africa, namely, the structure, the process and the outcomes. It focuses particularly on the factors that contribute to the quality of the structure and the process. For this purpose, two measures of quality are used, i.e. availability (in relation to the structure) and acceptability (in relation to the process). The authors identify factors that affect the availability and acceptability of AHC and suggest ways in which they, and hence the quality of AHC provided to smallholders in Africa, can be improved.
Based on a literature review of the occurrence of polychlorinated biphenyl (PCB) congeners in commercial formulations, environmental and biological samples and human tissues, and a consideration of the relative toxicity and persistence of the congeners, suggestions are made as to the most relevant components to be quantified by a selective congener analytical approach to human foodstuffs and tissues. These criteria suggest congener numbers 28, 74, 77, 99, 105, 118, 126, 128, 138, 153, 156, 169, 170, 179 and 180 will give a measure of greater than 70% of the total PCB tissue burden in a sample and be of greatest toxicological significance. Additionally, congeners 8, 37, 44, 49, 52, 60, 66, 70, 82, 87, 101, 114, 158, 166, 183, 187 and 189 are considered because of their reported occurrence or toxicity.
Transverse gradient coils with co-axial return paths offer reduced acoustic noise compared with standard cylindrical gradient coils, due to local force balancing, and can also easily be made to have a length to diameter ratio that is less than one. Analytic expressions for the magnetic field and vector potential generated by this type of coil are described here, along with a formula for calculating the coil inductance. It is shown that these expressions allow the implementation of powerful analytic methods of coil design, as well as the incorporation of active magnetic screening. It is also demonstrated how the mathematics specifies the best parameters to use when designing coils with small numbers of elements. A head gradient coil for use at 3.0 T has been designed using the analytic approach described here. The process of coil design and construction is outlined and the performance of the coil in comparison with a similar standard cylindrical coil is described.
This paper describes the study population and the study design of the phase III field trail of the SPf66 vaccine in Brazil. Assessment of validity and precision principles necessary for the appropriate evaluation of the protective effect of the vaccine are discussed, as well as the results of the preliminary analyses of the gathered data. The analytical approach for the estimation of the protective effect of the vaccine is presented. This paper provides the conceptual framework for future publications.