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On Sample Size of the Kruskal-Wallis Test with Application to a Mouse Peritoneal Cavity Study

BIOMETRICS 2011年第1期67卷 213-224页

作者： Fan, Chunpeng Zhang, Donghui Zhang, Cun-Hui Sanofi Aventis BX2 416A Dept Biostat & Programming Bridgewater NJ 08807 USA Rutgers State Univ Dept Stat & Biostat Piscataway NJ 08854 USA

As the nonparametric generalization of the one-way analysis of variance model, the Kruskal-Wallis test applies when the goal is to test the difference between multiple samples and the underlying population distributions are nonnormal or unknown. Although the Kruskal-Wallis test has been widely used for data analysis, power and sample size methods for this test have been investigated to a much lesser extent. This article proposes new power and sample size calculation methods for the Kruskal-Wallis test based on the pilot study in either a completely nonparametric model or a semiparametric location model. No assumption is made on the shape of the underlying population distributions. Simulation results show that, in terms of sample size calculation for the Kruskal-Wallis test, the proposed methods are more reliable and preferable to some more traditional methods. A mouse peritoneal cavity study is used to demonstrate the application of the methods.

关键词： Kruskal-Wallis test Location shift alternatives Power Sample size

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An Alternative Way to Classify Missing Data Mechanism in Clinical TrialsA Dialogue on Missing Data

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2011年第2期21卷 355-361页

作者： Wei, Lynn Sanofi Aventis US Biostat & Programming Bridgewater NJ 08807 USA

Statisticians in pharmaceutical field are constantly challenged by missing data caused by patient dropout in clinical trials. What the targeted population parameter for statistical inference should be when missing data are present has been a much-debated point. Many missing data methods aim at the so-called hypothetical parameter, i.e., treatment effect of a drug assuming no patients dropout from a clinical trial for the drug. Other methods intend to combine all dropout information into the treatment effect estimate. We believe that patient dropouts should not be treated equally when determining the population parameter of treatment effect. The objective of clinical trials, after all, is to evaluate a drug's effect on patients. Dropouts due to drug-related reasons such as drug-induced adverse experience are part of the drug's attributes, while dropout due to non-drug-related reasons, such as protocol deviation, are not inherent characteristics of the drug. Hence we propose to classify the patient dropouts into two classes: intrinsic (drug-related) and extrinsic (non-drug-related) dropouts. The former should be taken into account when defining the population parameter of the treatment effect, while the latter should not be. This classification will help determine a target population parameter that depicts a fair picture of a drug's effect, while the common classification of missing data as missing completely random (MCAR), missing at random (MAR), and missing not at random (MNAR) will help define appropriate statistical approach to analysis when missing data exist. Other related issues, such as statistical inference under this classification and implementing the classification in real clinical trials, are also touched upon here.

关键词： Extrinsic Intrinsic Missing data in clinical trials

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Clinical and Statistical Assessment of Suicidal Ideation and Behavior in Pharmaceutical Trials

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CLINICAL PHARMACOLOGY & THERAPEUTICS 2011年第4期90卷 554-560页

作者： Gassmann-Mayer, C. Jiang, K. McSorley, P. Arani, R. DuBrava, S. Suryawanshi, S. Webb, D. M. Nilsson, M. Johnson & Johnson Pharmaceut Res & Dev LLC Clin Biostat Raritan NJ USA Sanofi Aventis Biostat & Programming Bridgewater NJ USA GlaxoSmithKline Neurosci Med Dev Ctr Stat & Programming Res Triangle Pk NC USA Bristol Myers Squibb Co Global Biometr Sci Pennington NJ USA Pfizer Inc Clin Stat New London CT USA Merck & Co Inc Late Dev Stat Rahway NJ 07065 USA Eli Lilly & Co Global Med Commun Indianapolis IN 46285 USA Eli Lilly & Co Global Stat Sci Steamboat Springs CO USA

In the past two decades, the potential association between the risk of suicidal ideation and behavior and the clinical use of pharmaceutical products has been debated among industry, regulators, and academia. A better understanding of the possible effects-favorable, unfavorable, or neutral-of pharmaceuticals on the risk of suicidal ideation and behavior may be required, especially for trials typically designed for other primary objectives. Here, a cross-industry statistical team provides recommendations that address the assessment, statistical analysis, interpretation, and utility of suicide-related data in pharmaceutical clinical trials. These recommendations are to evaluate suicidal ideation, suicidal behavior, and the two combined as end points;utilize standard scales to collect data prospectively;and analyze the data using several statistical methods. A more accurate assessment of the potential association between the use of pharmaceutical products and risk of suicide-related events will contribute to estimating the benefit/risk ratio and result in safer medicines for patients.

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Prediction of Human Oral Plasma Concentration-Time Profiles Using Preclinical Data Comparative Evaluation of Prediction Approaches in Early Pharmaceutical Discovery

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CLINICAL PHARMACOKINETICS 2011年第8期50卷 505-517页

作者： Van den Bergh, An Sinha, Vikash Gilissen, Ron Straetemans, Roe Wuyts, Koen Morrison, Denise Bijnens, Luc Mackie, Claire Johnson & Johnson Pharmaceut Res & Dev ADME TOX Dept B-2540 Beerse Belgium Johnson & Johnson Pharmaceut Res & Dev Dept Clin Pharmacol B-2540 Beerse Belgium Johnson & Johnson Pharmaceut Res & Dev Biostat & Programming Dept B-2540 Beerse Belgium

Background and Objectives: Empirically based methods remain one of our tools in human pharmacokinetic predictions. The Dedrick approach and the steady-state plasma drug concentration (C-ss)-mean residence time (MRT) approach are based on the assumption that concentration-time profiles are similar among species, including man, and that curves derived from a variety of animal species can be superimposed after mathematical transformation. In the Dedrick approach the transformation is based on the slope and intercept of the allometric relationship. The C-ss-MRT approach is based on the implementation of measured animal and predicted human MRT and dose/volume of distribution at steady state (V-ss). The aims of the present study were to compare the predictive performance of concentration-time profiles obtained by these approaches, to evaluate the prediction of individual pharmacokinetic parameters by these approaches and to further refine these approaches incorporating the experience from our previous work. Methods: A retrospective analysis using 35 proprietary compounds developed at Johnson & Johnson Pharmaceutical Research and Development was conducted to compare the accuracies of the Dedrick and C-ss-MRT approaches for predicting oral concentration-time profiles and pharmacokinetic parameters in man. In the first step, input for the transformation was based on simple allometry. Then we assessed whether both methods could be fine-tuned by systematically incorporating correction factors (maximum life span potential, brain weight and plasma protein binding), depending on the interspecies relationship. In addition, for the C-ss-MRT approach, we used formulas based on multivariate regression analysis as input for the transformation. Results: Inclusion of correction factors significantly improved the profile predictability for the Dedrick and C-ss-MRT approaches. This was mainly linked to an improved prediction of terminal elimination half-life (t(1/2)) MRT and the ratio bet

关键词： PLASMA (Ionized gases) PHARMACOKINETICS ALLOMETRY PHARMACEUTICAL research PROTEIN binding RETROSPECTIVE studies TRANSFORMATIONS (Mathematics)

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INCIDENCE AND RELEVANCE OF PROTEINURIA IN BEVACIZUMAB (BV)-TREATED PATIENTS (PTS): POOLED ANALYSIS FROM RANDOMIZED CONTROLLED TRIALS (RCTS)

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ANNALS OF ONCOLOGY 2012年 23卷 171-171页

作者： Lafayette, R. McCall, B. Li, N. F. Chu, L. Werner, P. Das, A. Glassock, R. J. Stanford Glomerular Dis Ctr Stanford CA USA Genentech Inc Oncol Prod Dev San Francisco CA 94080 USA Genentech Inc Biostat San Francisco CA 94080 USA Genentech Inc Global Prod Dev Biometr San Francisco CA 94080 USA F Hoffmann La Roche & Cie AG Stat Programming Anal Spa Basel Switzerland Genentech Inc PDCO San Francisco CA 94080 USA UCLA David Geffen Sch Med Laguna Niguel CA USA

Background Proteinuria (PU) is a recognized adverse event with BV treatment (tx); however it is not known if BV-related PU is associated with clinical outcomes. This analysis was undertaken to define the relationship between PU with BV tx and sequelae, including changes in kidney function. Methods A pooled safety database, comprising 22 phase 2/3 RCTs of BV across tumor types, was used to characterize PU events. Analysis pools were created based on data availability in individual studies. Raw and time-adjusted PU rates and data on the association between PU and arterial thromboembolic events (TEs), venous TEs, and infection were derived from Pool 1 (17 RCTs; n = 14,548). Data from Pool 2 (8 RCTs; n = 9,158) were used to estimate the association between lab-reported PU and changes in kidney function based on serum creatinine (sCr) levels. Severity of kidney function change was categorized using the RIFLE classification for acute kidney injury (AKI). Potential predictors of PU were also assessed. Results In Pool 1, the incidence rate of any-grade (gr) PU was 8.2% (733/8917) and 4.6% (257/5631) in BV and control pts, respectively; gr ≥3 PU occurred in 1.4% and 0.2%, respectively. Pts developing PU had a numerically increased rate of any-gr infection irrespective of tx (driven mostly by urinary tract infection); however, no association was found between PU and TEs (arterial or venous). In Pool 2, PU gr and tx appeared to slightly shift the rate of post-baseline AKI (Table). Evaluated risk factors (age, sex, history of hypertension or diabetes) were not found to be significantly predictive for gr ≥3 PU. Conclusions The use of laboratory events and pooled data confirm a modest increase in PU with BV tx. The development of PU in BV-treated pts was associated with a modest increase in the risk of infection, but not TEs, and a trend toward a decrease in kidney function. Whether these associations are causal cannot be determined by this analysis. Tx group Worst post-BL gr of

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Bleeding Risk in Patients With Atrial Fibrillation The AMADEUS Study

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CHEST 2011年第1期140卷 146-155页

作者： Lane, Deirdre A. Kamphuisen, Pieter W. Minini, Pascal Buller, Harry R. Lip, Gregory Y. H. Univ Birmingham City Hosp Ctr Cardiovasc Sci Birmingham B18 7QH W Midlands England Univ Amsterdam Acad Med Ctr Dept Vasc Med NL-1105 AZ Amsterdam Netherlands Sanofi Aventis Res & Dev Biostat & Programming Chilly Mazarin France

Objective: This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF). Methods: Post hoc analysis of 4,576 patients with AF (mean +/- SD age, 70.1 +/- 9.1 years;men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy). Results: A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and >= 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and >= 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year];adjusted hazard ratio, 2.01;95% CI, 0.94-4.30;P = .07). Conclusions: Combination antithrombotic therapy increases the risk of clinically relev

关键词： Aged Anticoagulants/adverse effects Anticoagulants/therapeutic use Atrial Fibrillation/complications Dose-Response Relationship, Drug Drug Therapy, Combination England/epidemiology England/epidemiology Female Hemorrhage/chemically induced Hemorrhage/epidemiology Humans Incidence Injections, Subcutaneous Male Oligosaccharides/administration & dosage Oligosaccharides/adverse effects Platelet Aggregation Inhibitors/administration & dosage Platelet Aggregation Inhibitors/adverse effects Prognosis Risk Assessment/methods Risk Factors Stroke/etiology Stroke/prevention & control Warfarin/adverse effects Warfarin/therapeutic use

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Impact of lenalidomide dose on progression-free survival in patients with relapsed or refractory multiple myeloma

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LEUKEMIA 2011年第10期25卷 1620-1626页

作者： Dimopoulos, M. A. Hussein, M. Swern, A. S. Weber, D. Univ Athens Sch Med Dept Clin Therapeut Alexandra Hosp Athens 11528 Greece Celgene Corp Dept Med Affairs Summit NJ USA Celgene Corp Dept Stat Biostat & Programming Summit NJ USA Univ Texas Houston MD Anderson Canc Ctr Dept Lymphoma & Myeloma Houston TX 77030 USA

This analysis assessed the effect of lenalidomide on progression-free survival (PFS). Patients with relapsed or refractory multiple myeloma (RRMM) who received lenalidomide plus dexamethasone in the MM-009 and MM-010 trials were pooled and those who had not progressed and were still receiving lenalidomide at 12 months were included. The median follow-up of surviving patients was 48 months. Of 353 patients who received lenalidomide plus dexamethasone, 116 (33%) had not progressed. Overall, 52 patients (45%) had no dose reductions, 25 (22%) had dose reductions >= 12 months and 39 (34%) had dose reductions before 12 months. Patients who had dose reductions >= 12 months had a significantly longer median PFS than those who had reductions before 12 months (P = 0.007) or no dose reductions (P = 0.039) (not reached vs 28.0 vs 36.8 months, respectively). In a multivariate Cox regression model, dose reduction >= 12 months was an independent predictor of improved PFS (hazard ratio, 0.47;95% confidence interval, 0.23-0.98) after adjusting for patient characteristics. The data suggest that to achieve maximum PFS benefit, patients with RRMM should be treated for >= 12 months with full-dose lenalidomide plus dexamethasone. Thereafter, patients may benefit from lower-dose continued therapy;prospective studies are needed to confirm these findings. Leukemia (2011) 25, 1620-1626;doi:10.1038/leu.2011.126;published online 12 July 2011

关键词： dexamethasone lenalidomide multiple myeloma progression-free survival refractory relapsed

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Sample size considerations for Japanese patients in a multi-regional trial based on MHLW guidance

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PHARMACEUTICAL STATISTICS 2010年第2期9卷 100-112页

作者： Quan, Hui Zhao, Peng-Liang Zhang, Ji Roessner, Martin Aizawa, Kyo Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

Since the publication of the International Conference on Harmonization E5 guideline, new drug approvals in Japan based on the bridging strategy have been increasing. To further streamline and expedite new drug development in Japan, the Ministry of Health, Labour and Welfare, the Japanese regulatory authority, recently issued the 'Basic Principles on Global Clinical Trials' guidance to promote Japan's participation in multi-regional trials. The guidance, in a Q&A format, provides two methods as examples for recommending the number of Japanese patients in a multi-regional trial. Method l in the guidance is the focus of this paper. We derive formulas for the sample size calculations for normal, binary and survival endpoints. Computations and simulation results are provided to compare different approaches. Trial examples are used to illustrate the applications of the approaches. Copyright (C) 2009 John Wiley & Sons, Ltd.

关键词： bridging study ethnic effect delta method survival endpoint risk reduction

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Use of the Average Baseline Versus the Time-Matched Baseline in Parallel Group Thorough QT/QTc Studies

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2010年第3期20卷 665-682页

作者： Meng, Zhaoling Quan, Hui Fan, Li Kringle, Robert Sun, Gordon Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

Using historical studies, we compared the impact of using the average baseline or time-matched baseline on diurnal effect correction, treatment effect estimation, and analysis of variance/covariance (ANOVA/ANCOVA) efficiency in a parallel thorough QT/QTc (TQT) study. Under a multivariate normal distribution assumption, we derived conditions for achieving unbiasness and better efficiency when using the average baseline, and confirmed these conditions using historical TQT studies. Furthermore, simulations were conducted under the randomized trial with and without observed imbalanced baseline settings. We conclude that the analyses using average baseline yield better efficiency and unbiased or less biased results under our TQT study conditions.

关键词： ANCOVA ANOVA Bias Diurnal effect correction Efficiency

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Multiple Comparisons in Microarray Data Analysis

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STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2010年第3期2卷 368-382页

作者： Zhang, Donghui Liu, Li Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA

Multiplicity is a challenging statistical issue in drug discovery, and a particular example is microarray study. The traditional approach of controlling of the family-wise error rate (FWER) is conservative when the number of tests is large. A more appropriate approach is to control the false discovery rate (FDR). Since the development of the Benjamini and Hochberg (BH) FDR procedure in 1995, many modifications have been proposed aimed at relaxing the requirement for independent test statistics or improving the power of the BH FDR procedure. Comparisons of these procedures in the current literature are not comprehensive and the conclusions on performances are inconsistent. The objectives of this article are three-fold: (a) to perform a more comprehensive comparison of extant multiple testing procedures using two real microarray datasets and various simulated data sets;(b) to explore potential reasons for the inconsistencies in published simulation results;and (c) to identify suitable FDR procedures under different scenarios according to covariance structure, percent of true null hypotheses among multiple tests, and sample size.

关键词： False discovery rate Family-wise error rate Multiple testing

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