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Evaluating longitudinal markers under two-phase study designs

biostatISTICS 2019年第3期20卷 485-498页

作者： Maziarz, Marlena Cai, Tianxi Qi, Li Lok, Anna S. Zheng, Yingye Univ Washington Dept Biostat 1705 NE Pacific St Seattle WA 98195 USA Harvard TH Chan Sch Publ Hlth Dept Biostat 677 Huntington Ave Boston MA 02115 USA Sanofi Biostat & Programming 55 Corp Dr Bridgewater NJ 08807 USA Univ Michigan Dept Gastroenterol 1500 E Med Ctr Dr Ann Arbor MI 48109 USA Fred Hutchinson Canc Res Ctr Dept Biostat 1100 Fairview Ave N Seattle WA 98109 USA

Little attention has been given to the design of efficient studies to evaluate longitudinal biomarkers. Measuring longitudinal markers on an entire cohort is cost prohibitive and, especially for rare outcomes such as cancer, may be infeasible. Thus, methods for evaluation of longitudinal biomarkers using efficient and cost-effective study designs are needed. Case cohort (CCH) and nested case-control (NCC) studies allow investigators to evaluate biomarkers rigorously and at reduced cost, with only a small loss in precision. In this article, we develop estimators of several measures to evaluate the accuracy and discrimination of predicted risk under CCH and NCC study designs. We use double inverse probability weighting (DIPW) to account for censoring and sampling bias in estimation and inference procedures. We study the asymptotic properties of the proposed estimators. To facilitate inference using two-phase longitudinal data, we develop valid resampling-based variance estimation procedures under CCH and NCC. We evaluate the performance of our estimators under CCH and NCC using simulation studies and illustrate them on a NCC study within the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) clinical trial. Our estimators and inference procedures perform well under CCH and NCC, provided that the sample size at the time of prediction (effective sample size) is reasonable. These methods are widely applicable, efficient, and cost-effective and can be easily adapted to other study designs used to evaluate prediction rules in a longitudinal setting.

关键词： Biomarker evaluation Longitudinal and survival data Two-phase designs

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Design and monitoring of clinical trials with an interim analysis and a negative binomial endpoint

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CONTEMPORARY CLINICAL TRIALS 2024年 138卷 107467-107467页

作者： Quan, Hui Xu, Yuqing Liu, Ying Chen, Xun Sanofi Biostat & Programming 55 Corp Dr Bridgewater NJ 08807 USA

There are very rich publications devoted to group sequential design, adaptive design and trial monitoring for continuous, binary and time to event endpoints. Many authors also discuss fixed design, blinded sample size reestimation design and group sequential design for studies with a negative binomial outcome. Nonetheless, literature is sparse in adaptive design for a trial with a negative binomial endpoint. The features of such an endpoint in a flexible trial design setting remains inadequately understood. In this research, we seek to bridge this knowledge gap by offering a thorough examination of utilizing data components from a two-stage adaptive design for unblinded conditional power calculation and corresponding sample size re-estimation. We also provide expression for calculating the probability of meeting the futility criterion to determine the appropriate timing for the interim analysis. To evaluate the performance of the design, we conduct simulations to assess its operation characteristics. Finally, we provide a helpful and illustrative example to demonstrate the practical applications of the methods.

关键词： Conditional power Probability of success Independent increment Adaptive design Posterior distribution Decision making

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ClonoCalc and ClonoPlot: immune repertoire analysis from raw files to publication figures with graphical user interface

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BMC BIOINFORMATICS 2017年第1期18卷 1-6页

作者： Faehnrich, Anke Krebbel, Moritz Decker, Normann Leucker, Martin Lange, Felix D. Kalies, Kathrin Moeller, Steffen Inst Anat Ratzeburger Allee 160 D-23562 Lubeck Germany Inst Software Engn & Programming Languages Ratzeburger Allee 160 D-23562 Lubeck Germany Inst Biostat & Informat Med & Ageing Res Ernst Heydemann Str 8 D-18057 Rostock Germany

Background: Next generation sequencing (NGS) technologies enable studies and analyses of the diversity of both T and B cell receptors (TCR and BCR) in human and animal systems to elucidate immune functions in health and disease. Over the last few years, several algorithms and tools have been developed to support respective analyses of raw sequencing data of the immune repertoire. These tools focus on distinct aspects of the data processing and require a strong bioinformatics background. To facilitate the analysis of T and B cell repertoires by less experienced users, software is needed that combines the most common tools for repertoire analysis. Results: We introduce a graphical user interface (GUI) providing a complete analysis pipeline for processing raw NGS data for human and animal TCR and BCR clonotype determination and advanced differential repertoire studies. It provides two applications. ClonoCalc prepares the raw data for downstream analyses. It combines a demultiplexer for barcode splitting and employs MiXCR for paired- end read merging and the extraction of human and animal TCR/BCR sequences. ClonoPlot wraps the R package tcR and further contributes self-developed plots for the descriptive comparative investigation of immune repertoires. Conclusion: This workflow reduces the amount of programming required to perform the respective analyses and supports both communication and training between scientists and technicians, and across scientific disciplines. The Open Source development in Java and R is modular and invites advanced users to extend its functionality. Software and documentation are freely available at https://***/ClonoSuite/clonocalc-plot.

关键词： Next-generation sequencing Immune repertoire analysis Graphical user interface

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Phase I study of aflibercept in combination with docetaxel in Japanese patients with advanced solid malignancies

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INVESTIGATIONAL NEW DRUGS 2022年第5期40卷 1032-1041页

作者： Sunakawa, Yu Takahashi, Keishiro Kawaguchi, Osamu Yamamoto, Nobuyuki St Marianna Univ Dept Clin Oncol Sch Med Kawasaki Kanagawa Japan Sanofi Res & Dev Tokyo Japan Sanofi Biostat & Programming Tokyo Japan Wakayama Med Univ Hosp Dept Internal Med 3 Wakayama Japan

Angiogenesis is a hallmark of cancer development. This study sought to determine the recommended dose of aflibercept, a recombinant fusion protein targeting VEGF-A, VEGF-B and placental growth factor (PlGF), combined with docetaxel in Japanese patients with advanced solid malignancies. This phase I study was planned to include 12 patients following a 3 + 3 algorithm to determine the maximum tolerated dose of aflibercept combined with docetaxel in patients with metastatic or unresectable solid tumors (trial registration: NCT00545246). Docetaxel (75 mg/m(2) every 3 weeks or 60 mg/m(2) after protocol amendment) was combined with escalating doses of aflibercept (2, 4 and 6 mg/kg every 4 weeks). Free and VEGF-bound aflibercept were measured to assess free aflibercept in excess of the VEGF-bound form. At the starting dose of the combination, 3 of 6 patients treated experienced febrile neutropenia. After reducing the docetaxel dose to 60 mg/m(2) in step 2 and permitting therapeutic granulocyte colony-stimulating factor (G-CSF) use, 2 of 3 patients in both cohorts experienced febrile neutropenia. Five patients (42%) had a partial response and 4 patients had stable disease (33%). Free aflibercept in excess of the VEGF-bound form was not maintained at this dose level. The dose limiting toxicity (DLT) of aflibercept combined with docetaxel was febrile neutropenia, which occurred in 2 of 3 Japanese patients at the lowest aflibercept dose level (2 mg/kg) combined with docetaxel (60 mg/m(2)) and therapeutic G-CSF use. A recommended dose for further studies was not determined because of the DLT at the starting dose.

关键词： Aflibercept Docetaxel Dose escalation Japanese VEGF Trap

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STATISTICAL POWER ANALYSIS FOR ONE-WAY ANALYSIS OF VARIANCE - A COMPUTER-PROGRAM

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BEHAVIOR RESEARCH METHODS INSTRUMENTS & COMPUTERS 1990年第3期22卷 271-282页

作者： BORENSTEIN, M COHEN, J ROTHSTEIN, HR POLLACK, S KANE, JM BIOSTAT PROGRAMMING ASSOCIATES TEANECKNJ NYU NEW YORKNY 10003 CUNY BERNARD M BARUCH COLL NEW YORKNY 10010 ST JOHNS UNIV JAMAICANY 11439

To facilitate the computation of statistical power for analysis of variance, Cohen developed the index of effect sizef, defined as theSD between groups divided by theSD within groups. A microcomputer program for statistical power allows the user to compute the value off in any of several ways: by specifying the mean andSD for every cell in the ANOVA; by specifying the mean value for the two extreme cells and the pattern of dispersion for the remaining cells; by estimating the proportion of variance in the dependent variable that will be explained by group membership; and/or with reference to conventions for small, medium, and large effects. The program will compute power for any single set of parameters; it will also allow the user to generate tables and graphs showing how power will vary as a function of effect size, sample size, andα.

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A Placebo-Controlled Study Evaluating the Efficacy and Safety of Flexible-Dose Desvenlafaxine Treatment in Outpatients with Major Depressive Disorder

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CNS SPECTRUMS 2009年第1期14卷 41-50页

作者： Feiger, Alan D. Tourian, Karen A. Rosas, Gregory R. Padmanabhan, S. Krishna Univ Colorado Depress Ctr Aurora CO USA Wyeth Ayerst Res Neurosci Clin Res & Dev Collegeville PA USA Wyeth Ayerst Res Clin Res & Dev Global Biostat & Programming Stat Res & Applicat Collegeville PA USA

Introduction: This research compares the efficacy and safety of desvenlafaxine (administered as desvenlafaxine succinate) versus placebo in treating major depressive disorder. Methods: In this randomized, double-blind study, outpatients with major depressive disorder >= 18 years of age received desvenlafaxine 200-400 mg/day or placebo for 8 weeks. Efficacy endpoints included (primary) change in 17-item Hamilton Rating Scale for Depression score at the final evaluation (last observation carried forward, analysis of covariance) and (secondary) Clinical Global Impressions-Improvement and.-Severity of Illness scales. Results: The difference between desvenlafaxine (n=117) and placebo (n=118) on the primary endpoint was not significant (-9.1 vs -7.5, P=.078). Week 8 observed cases (desvenlafaxine, n=80;placebo, n=94) results were significant (-10.7 vs -7.9, P=.008). Differences at the final evaluation (last observation carried forward) were significant for Clinical Global Impressions-Improvement (2.9 vs 2.5, P=.037) and Clinical Global Impressions-Severity of Illness (-1.9 vs -1.2, P=.041). Discontinuation rates due to adverse events (AEs) were 12% and 3% for desvenlafaxine and placebo, respectively (P=.008). The most frequently reported AE associated with desvenlafaxine was nausea 36% vs 9% [placebo]). Conclusion: In this study, the primary analysis did not show significant differences between desvenlafaxine and placebo;discontinuations due to AEs associated with the desvenlafaxine dose range may have contributed to the lack of statistical separation.

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Information fraction estimation: Strategies for a phase 3 non-inferiority maximum duration design with time to event outcome

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PHARMACEUTICAL STATISTICS 2023年第6期22卷 1031-1045页

作者： Dang, Ha M. Krailo, Mark D. Alonzo, Todd A. Mack, Wendy J. Kairalla, John A. Univ Southern Calif Dept Populat & Publ Hlth Sci Los Angeles CA USA Childrens Oncol Grp Monrovia CA USA Johnson & Johnson Med Devices Co Biostat Programming & Data Management 29B Technol Dr Irvine CA 92618 USA Univ Florida Coll Med Dept Biostat Gainesville FL USA Univ Florida Coll Publ Hlth & Hlth Profess Dept Biostat Gainesville FL USA

There is considerable debate surrounding the choice of methods to estimate information fraction for futility monitoring in a randomized non-inferiority maximum duration trial. This question was motivated by a pediatric oncology study that aimed to establish non-inferiority for two primary outcomes. While non-inferiority was determined for one outcome, the futility monitoring of the other outcome failed to stop the trial early, despite accumulating evidence of inferiority. For a one-sided trial design for which the intervention is inferior to the standard therapy, futility monitoring should provide the opportunity to terminate the trial early. Our research focuses on the Total Control Only (TCO) method, which is defined as a ratio of observed events to total events exclusively within the standard treatment regimen. We investigate its properties in stopping a trial early in favor of inferiority. Simulation results comparing the TCO method with alternative methods, one based on the assumption of an inferior treatment effect (TH0), and the other based on a specified hypothesis of a non-inferior treatment effect (THA), were provided under various pediatric oncology trial design settings. The TCO method is the only method that provides unbiased information fraction estimates regardless of the hypothesis assumptions and exhibits a good power and a comparable type I error rate at each interim analysis compared to other methods. Although none of the methods is uniformly superior on all criteria, the TCO method possesses favorable characteristics, making it a compelling choice for estimating the information fraction when the aim is to reduce cancer treatment-related adverse outcomes.

关键词： futility analysis group sequential analysis information fraction interim monitoring analysis maximum duration clinical trials non-inferiority design pediatric oncology survival outcome trials

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Performance of epistasis detection methods in semi-simulated GWAS

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BMC BIOINFORMATICS 2018年第1期19卷 1-17页

作者： Chatelain, Clement Durand, Guillermo Thuillier, Vincent Auge, Franck SANOFI R&D Translat Sci F-91385 Chilly Mazarin France Univ Paris 06 Lab Probabilites Modeles Aleatoires 4 Pl Jussieu F-75252 Paris 05 France SANOFI R&D Biostat & Programming F-91385 Chilly Mazarin France

Background: Part of the missing heritability in Genome Wide Association Studies (GWAS) is expected to be explained by interactions between genetic variants, also called epistasis. Various statistical methods have been developed to detect epistasis in case-control GWAS. These methods face major statistical challenges due to the number of tests required, the complexity of the Linkage Disequilibrium (LD) structure, and the lack of consensus regarding the definition of epistasis. Their limited impact in terms of uncovering new biological knowledge might be explained in part by the limited amount of experimental data available to validate their statistical performances in a realistic GWAS context. In this paper, we introduce a simulation pipeline for generating real scale GWAS data, including epistasis and realistic LD structure. We evaluate five exhaustive bivariate interaction methods, fastepi, GBOOST, SHEsisEpi, DSS, and IndOR. Two hundred thirty four different disease scenarios are considered in extensive simulations. We report the performances of each method in terms of false positive rate control, power, area under the ROC curve (AUC), and computation time using a GPU. Finally we compare the result of each methods on a real GWAS of type 2 diabetes from the Welcome Trust Case Control Consortium. Results: GBOOST, SHEsisEpi and DSS allow a satisfactory control of the false positive rate. fastepi and IndOR present an increase in false positive rate in presence of LD between causal SNPs, with our definition of epistasis. DSS performs best in terms of power and AUC in most scenarios with no or weak LD between causal SNPs. All methods can exhaustively analyze a GWAS with 6.10(5) SNPs and 15,000 samples in a couple of hours using a GPU. Conclusion: This study confirms that computation time is no longer a limiting factor for performing an exhaustive search of epistasis in large GWAS. For this task, using DSS on SNP pairs with limited LD seems to be a good strategy to achiev

关键词： Genome-wide association studies Epistasis Simulation

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Some Multiplicity Adjustment Procedures for Clinical Trials with Sequential Design and Multiple Endpoints

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STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2024年第1期16卷 104-115页

作者： Luo, Xiaodong Quan, Hui Sanofi US Biostat & Programming 55 Corp Dr Bridgewater NJ 08807 USA

This article proposes some new multiplicity adjustment procedures for clinical trials with multiple endpoints and multiple interim analyses. The proposed sequential procedures, adapting the popular multiple comparison procedures for fixed time-point design and using a-spending for each endpoint, are shown to strongly control the family-wise Type-1 error rate and provide powerful yet versatile multiplicity adjustment solutions for monitoring multiple endpoints via interim analyses.

关键词： Generalized Simes inequality Group-sequential p-values Multiplicity q-values early submission alpha-propagation

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Statistical Monitoring in Clinical Trials: Best Practices for Detecting Data Anomalies Suggestive of Fabrication or Misconduct

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THERAPEUTIC INNOVATION & REGULATORY SCIENCE 2016年第2期50卷 144-154页

作者： Knepper, David Lindblad, Anne S. Sharma, Gaurav Gensler, Gary R. Manukyan, Zorayr Matthews, Abigail G. Seifu, Yodit Drug Dev Operat 1900 Plaza 5 Jersey City NJ 07311 USA Emmes Corp Rockville MD USA Pfizer Global Res & Dev Biostat Cambridge MA USA Allergan Pharmaceut Inc Stat Sci & Programming Bridgewater NJ USA

Background: Traditional site-monitoring techniques are not optimal in finding data fabrication and other nonrandom data distributions with the greatest potential for jeopardizing the validity of study results. TransCelerate BioPharma conducted an experiment testing the utility of statistical methods for detecting implanted fabricated data and other signals of noncompliance. Methods: TransCelerate tested statistical monitoring on a data set from a chronic obstructive pulmonary disease (COPD) clinical study with 178 sites and 1554 subjects. Fabricated data were selectively implanted in 7 sites and 43 subjects by expert clinicians in COPD. The data set was partitioned to simulate studies of different sizes. Analyses of vital signs, spirometry, visit dates, and adverse events included distributions of standard deviations, correlations, repeated values, digit preference, and outlier/inlier detection. An interpretation team, including clinicians, statisticians, site monitoring, and data management, reviewed the results and created an algorithm to flag sites for fabricated data. Results: The algorithm identified 11 sites (19%), 19 sites (31%), 28 sites (16%), and 45 sites (25%) as having potentially fabricated data for studies 2A, 2, 1A, and 1, respectively. For study 2A, 3 of 7 sites with fabricated data were detected, 5 of 7 were detected for studies 2 and 1A, and 6 of 7 for study 1. Except for study 2A, the algorithm had good sensitivity and specificity (>70%) for identifying sites with fabricated data. Conclusions: We recommend a cross-functional, collaborative approach to statistical monitoring that can adapt to study design and data source and use a combination of statistical screening techniques and confirmatory graphics.

关键词： statistical monitoring central monitoring risk-based monitoring fabrication fraud misconduct TransCelerate

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