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Empirical shrinkage estimator for consistency assessment of treatment effects in multi-regional clinical trials

STATISTICS IN MEDICINE 2013年第10期32卷 1691-1706页

作者： Quan, Hui Li, Mingyu Shih, Weichung Joe Ouyang, Soo Peter Chen, Joshua Zhang, Ji Zhao, Peng-Liang Sanofi Biostat & Programming Bridgewater NJ 08807 USA Celgene Corp Biostat & Programming Basking Ridge NJ 07920 USA UMDNJ Sch Publ Hlth Dept Biostat Piscataway NJ 08854 USA Merck Res Labs Rahway NJ 07065 USA

Multi-regional clinical trials have been widely used for efficient global new drug developments. Both a fixed-effect model and a random-effect model can be used for trial design and data analysis of a multi-regional clinical trial. In this paper, we first compare these two models in terms of the required sample size, type I error rate control, and the interpretability of trial results. We then apply the empirical shrinkage estimation approach based on the random-effect model to two criteria of consistency assessment of treatment effects across regions. As demonstrated in our computations, compared with the sample estimator, the shrinkage estimator of the treatment effect of an individual region borrowing information from the other regions is much closer to the estimator of the overall treatment effect, has smaller variability, and therefore provides much higher probability for demonstrating consistency. We use a multinational trial example with time to event endpoint to illustrate the application of the method. Copyright (c) 2012 John Wiley & Sons, Ltd.

关键词： sample size type I error rate random-effect model weighted estimator

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Robust methods for population stratification in genome wide association studies

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BMC BIOINFORMATICS 2013年第1期14卷 1-12页

作者： Liu, Li Zhang, Donghui Liu, Hong Arendt, Christopher Dept Biostat & Programming Bridgewater NJ 08807 USA Bioinnovat Grp Sanofi Biotherapeut Cambridge MA 02142 USA

Background: Genome-wide association studies can provide novel insights into diseases of interest, as well as to the responsiveness of an individual to specific treatments. In such studies, it is very important to correct for population stratification, which refers to allele frequency differences between cases and controls due to systematic ancestry differences. Population stratification can cause spurious associations if not adjusted properly. The principal component analysis (PCA) method has been relied upon as a highly useful methodology to adjust for population stratification in these types of large-scale studies. Recently, the linear mixed model (LMM) has also been proposed to account for family structure or cryptic relatedness. However, neither of these approaches may be optimal in properly correcting for sample structures in the presence of subject outliers. Results: We propose to use robust PCA combined with k-medoids clustering to deal with population stratification. This approach can adjust for population stratification for both continuous and discrete populations with subject outliers, and it can be considered as an extension of the PCA method and the multidimensional scaling (MDS) method. Through simulation studies, we compare the performance of our proposed methods with several widely used stratification methods, including PCA and MDS. We show that subject outliers can greatly influence the analysis results from several existing methods, while our proposed robust population stratification methods perform very well for both discrete and admixed populations with subject outliers. We illustrate the new method using data from a rheumatoid arthritis study. Conclusions: We demonstrate that subject outliers can greatly influence the analysis result in GWA studies, and propose robust methods for dealing with population stratification that outperform existing population stratification methods in the presence of subject outliers.

关键词： Population structure Population stratification Robust principal component analysis Resampling by half means Outlier detection GWA studies

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A Comparison of Bias-Corrected Covariance Estimators for Generalized Estimating Equations

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2013年第5期23卷 1172-1187页

作者： Fan, Chunpeng Zhang, Donghui Zhang, Cun-Hui Sanofi US Inc Dept Biostat & Programming Bridgewater NJ 08807 USA Rutgers State Univ Dept Stat & Biostat Piscataway NJ USA

Although asymptotically the sandwich covariance estimator is consistent and robust with respect to the selection of the working correlation matrix, when the sample size is small, its bias may not be negligible. This article compares the small sample corrections for the sandwich covariance estimator as well as the inferential procedures proposed by Mancl and DeRouen (2001), Kauermann and Carroll (2001), Fay and Graubard (2001), and Fan et al. (2012). Simulation studies show that when using a maximum likelihood method to estimate the covariance parameters and using the between-within method for the denominator degrees of freedom when making inference, the Kauermann and Carroll method is preferred in the investigated balanced logistic regression and the Mancl and DeRouen and Fan et al. methods are preferred in the investigated proportional odds model. A collagen-induced arthritis study is employed to demonstrate the application of the methods.

关键词： Empirical covariance estimator GEE Sandwich covariance estimator

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EFFICACY OF A FIBER RICH BEVERAGE IN REDUCTION OF POST PRANDIAL GLUCOSE & TRIGLYCERIDE SPIKES

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DIABETES RESEARCH AND CLINICAL PRACTICE 2014年 106卷 S50-S50页

作者： Kalita, S. Bhoite, R. Ghosh, S. Jain, R. Midgley, D. GSK Nutr & Med Affairs Gurgaon India GSK Clin Operat Gurgaon India GSK Biostat Gurgaon India GSK Data & Programming Operat Gurgaon India

PO007

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Considerations for Design and Data Analysis of Noninferiority/Superiority Cardiovascular Trials

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2013年第1期23卷 239-260页

作者： Quan, Hui Li, Mingyu Zhao, Peng-Liang Cho, Meehyung Zhang, Ji Wu, Yujun Sanofi Biostat & Stat Programming Bridgewater NJ 08807 USA Celgene Corp Basking Ridge NJ USA

The Food and Drug Administration (FDA) guidance for evaluating cardiovascular (CV) risk in new antidiabetic therapies to treat type 2 diabetes released in December 2008 recommends that sponsors conduct appropriate data analysis to rule out CV safety concerns for drugs treating type 2 diabetes. CV trials of antidiabetic drugs and drugs of other indications for chronic conditions are usually large-scale/long-term trials and can be designed as adaptive noninferiority/superiority trials. In these trials, treatment effect may not manifest immediately after patients take study medication and there will be a dilution in treatment effect after treatment discontinuation. These factors should be taken into account for more precise planning of study sample size and timeline. In this paper, we first derive closed-form formulas for the number of events and total exposure as functions of many other trial parameters. We then outline some considerations for the design of an adaptive noninferiority/superiority CV trial based on ideas of other authors. We also use an example to illustrate the application of the methods.

关键词： Conditional power Diluted treatment effect Exposure adjusted event rate ITT analysis Treatment emergent analysis

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The effects of teriflunomide on lymphocyte subpopulations in human peripheral blood mononuclear cells in vitro

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JOURNAL OF NEUROIMMUNOLOGY 2013年第1-2期265卷 82-90页

作者： Li, Li Liu, Jingchun Delohery, Thomas Zhang, Donghui Arendt, Christopher Jones, Catherine Sanofi BioInnovat Grp Cambridge MA 02139 USA Sanofi Global Biostat & Programming Bridgewater NJ USA

Teriflunomide is an inhibitor of dihydro-orotate dehydrogenase (DHODH), and is hypothesized to ameliorate multiple sclerosis by reducing proliferation of stimulated lymphocytes. We investigated teriflunomide's effects on proliferation, activation, survival, and function of stimulated human peripheral blood mononuclear cell subsets in vitro. Teriflunomide had little/no impact on lymphocyte activation but exerted significant dose-dependent inhibition of T- and B-cell proliferation, which was uridine-reversible (DHODH-dependent). Viability analyses showed no teriflunomide-associated cytotoxicity. Teriflunomide significantly decreased release of several pro-inflammatory cytokines from activated monocytes in a DHODH-independent fashion. In conclusion, teriflunomide acts on multiple immune cell types and processes via DHODH-dependent and independent mechanisms. (C) 2013 Elsevier B.V. All rights reserved.

关键词： Multiple sclerosis Immunomodulation Anti-inflammatory Anti-proliferative CNS De novo pyrimidine synthesis

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Phase I clinical and pharmacokinetic study of ombrabulin (AVE8062) combined with cisplatin/docetaxel or carboplatin/paclitaxel in patients with advanced solid tumors

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INVESTIGATIONAL NEW DRUGS 2014年第6期32卷 1188-1196页

作者： Bahleda, Rastislav Sessa, Cristiana Del Conte, Gianluca Gianni, Luca Capri, Giuseppe Varga, Andrea Oprea, Corina Daglish, Byzance Hospitel, Marie Soria, Jean-Charles Univ Paris 11 Drug Dev Dept DITEP F-94805 Villejuif France Oncol Inst Southern Switzerland Bellinzona Switzerland Ist Sci San Raffaele Dept Med Oncol I-20132 Milan Italy Natl Canc Inst I-20133 Milan Italy Sanofi Div Oncol Vitry Sur Seine France Sanofi Operat Unit Vitry Sur Seine France Sanofi Biostat & Programming Vitry Sur Seine France Hosp San Raffaele I-20132 Milan Italy

Purpose Preclinical evidence supports synergy between the vascular disrupting agent ombrabulin and various chemotherapy agents. Ombrabulin was combined with two standard taxane/platinum doublets in a phase I study to determine the recommended combination doses. Methods Ombrabulin (30-min infusion, day 1 every 3 weeks) was escalated from 15.5 to 35 mg/m(2) with two chemotherapy doublets;OCD, 75 mg/m(2) cisplatin (C), day 1 (cohort 1) or day 2 (cohort 2) with 60/75 mg/m(2) docetaxel (D), day 2;and OCP, AUC5/6 carboplatin (C) and paclitaxel (P) 175 mg/m(2) (cohort 3) or 200 mg/m(2) (cohort 4), day 2. Safety, pharmacokinetics, and tumor response were evaluated. Results Sixty-nine patients were treated (32 OCD, 37 OCP). Four had DLTs in cycle 1, two in cohort 1 (grade 4 febrile neutropenia, grade 4 pulmonary embolism) and one each in cohorts 2 (grade 3 ALT elevation) and 4 (grade 3 peripheral ischemia). Ombrabulin escalation in cohorts 2, 3 and 4 was halted at the highest planned dose (35 mg/m(2)). Asthenia, nausea, paresthesia, alopecia, vomiting, and stomatitis were common, as was grade 3-4 neutropenia. Ombrabulin clearance was high with a short terminal half-life and a medium volume of distribution. Pharmacokinetic analysis showed no clinically relevant drug interactions between the taxane-platinum doublet and ombrabulin or its active metabolite RPR258063, however docetaxel and carboplatin pharmacokinetics were slightly altered. One complete and 15 partial responses (10 OCD, 5 OCP;median duration 5.5 and 4.4 months, respectively) were reported. Conclusions The addition of ombrabulin to standard doses of cisplatin/docetaxel or carboplatin/paclitaxel proved feasible with manageable overlapping toxicities but appears to have limited impact on the efficacy of these doublets. Recommended combination doses are 35 mg/m(2) ombrabulin with 75 mg/m(2) cisplatin/75 mg/m(2) docetaxel or 200 mg/m(2) paclitaxel/AUC6 carboplatin, every 3 weeks.

关键词： Ombrabulin Vascular disrupting agent Chemotherapy Platinum Taxane

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Linear Transformation Model With Parametric Covariate Transformations

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JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION 2013年第502期108卷 701-712页

作者： Fan, Chunpeng Fine, Jason P. Sanofi US Inc Dept Biostat & Programming Bridgewater NJ 08807 USA Univ N Carolina Dept Biostat Chapel Hill NC 27599 USA

The traditional linear transformation model assumes a linear relationship between the transformed response and the covariates. However, in real data, this linear relationship may be violated. We propose a linear transformation model that allows parametric covariate transformations to recover the linearity. Although the proposed generalization may seem rather simple, the inferential issues are quite challenging due to loss of identifiability under the null of no effects of transformed covariates. This article develops tests for such hypotheses. We establish rigorous inferences for parameters and the unspecified transformation function when the transformed covariates have nonzero effects. The estimates and tests perform well in simulation studies using a realistic sample size. We also develop goodness-of-fit tests for the transformation and R-2 for model comparison. GAGurine data are used to illustrate the practical utility of the proposed methods.

关键词： Identifiability Profiling test R-2 Semiparametric model

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Parent-Targeted Mobile Phone Intervention to Increase Physical Activity in Sedentary Children: Randomized Pilot Trial

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JMIR MHEALTH AND UHEALTH 2014年第4期2卷 e48页

作者： Newton, Robert L., Jr. Marker, Arwen M. Allen, H. Raymond Machtmes, Ryan Han, Hongmei Johnson, William D. Schuna, John M., Jr. Broyles, Stephanie T. Tudor-Locke, Catrine Church, Timothy S. Pennington Biomed Res Ctr Populat & Publ Hlth 6400 Perkins Rd Baton Rouge LA 70808 USA Ohio Univ Patton Coll Educ Athens OH 45701 USA Pharmaceut Prod Dev Biostats & Programming Austin TX USA Pennington Biomed Res Ctr Biostat 6400 Perkins Rd Baton Rouge LA 70808 USA Oregon State Univ Exercise & Sport Sci Program Sch Biol & Populat Hlth Sci Corvallis OR 97331 USA

Background: Low levels of moderate-to-vigorous physical activity are associated with adverse health consequences. Objective: The intent of the study was to determine the feasibility and efficacy of a 12-week physical activity promotion program targeting children, which was delivered to parents through mobile phones. Methods: Potential participants were recruited through advertisements placed in the newspaper, local hospitals and schools, and an email listserv. Sedentary children aged 6-10 years were randomly assigned to a minimal (MIG) or intensive (IIG) intervention group. Parents in the MIG were given a goal to increase (within 1 month) and maintain their child's activity at 6000 pedometer steps/day above their baseline levels and to monitor their child's steps daily. Parents in the IIG were given the same steps/day and monitoring goals, in addition to text messages and articles containing additional behavioral strategies (based on the Social Cognitive Theory) designed to promote their child's physical activity. The intervention components were delivered via mobile phone. Anthropometrics, body composition, and questionnaires were administered in a clinic. Children wore a New Lifestyles pedometer (NL-1000) each day throughout the intervention and parents were to monitor their child's step counts daily. Results: Out of 59 children who screened for the study, a total of 27 children (mean age 8.7, SD 1.4 years;56%, 15/27 female;59%, 16/27 African American) were enrolled and completed the study. Overall, 97.90% (2220/2268;98.20%, 1072/1092 for MIG;97.60%, 1148/1176 for IIG) of expected step data were successfully entered by the parent or study coordinator. Parents in the MIG and IIG were sent approximately 7 and 13 text messages per week, respectively, averaged over the course of the study. IIG parents accessed an average of 6.1 (SD 4.4) articles over the course of the intervention and accessed a fewer number of articles in the last month compared to the first 2 months

关键词： mobile health physical activity intervention child parents pedometers text messaging

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A phase I pharmacokinetic study of the vascular disrupting agent ombrabulin (AVE8062) and docetaxel in advanced solid tumours

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BRITISH JOURNAL OF CANCER 2014年第9期110卷 2170-2177页

作者： Eskens, F. A. L. M. Tresca, P. Tosi, D. Van Doorn, L. Fontaine, H. Van der Gaast, A. Veyrat-Follet, C. Oprea, C. Hospitel, M. Dieras, V. Erasmus MC Canc Inst Dept Med Oncol NL-3000 CA Rotterdam Netherlands Inst Curie Clin Res Unit F-75231 Paris 05 France Sanofi Div Oncol F-94400 Vitry Sur Seine France Sanofi Trial Operat Dept F-94400 Vitry Sur Seine France Sanofi Div Drug Disposit DSAR F-91380 Chilly Mazarin France Sanofi Div Biostat & Programming F-94400 Vitry Sur Seine France

Background: The vascular disrupting agent ombrabulin shows synergy with docetaxel in vivo. Recommended phase II doses were determined in a dose escalation study in advanced solid tumours. Methods: Ombrabulin (30-min infusion, day 1) followed by docetaxel (1-h infusion, day 2) every 3 weeks was explored. Ombrabulin was escalated from 11.5 to 42mgm(-2) with 75 mgm(-2) docetaxel, then from 30 to 35 mgm(-2) with 100 mgm(-2) docetaxel. Recommended phase II dose cohorts were expanded. Results: Fifty-eight patients were treated. Recommended phase II doses were 35 mgm(-2) ombrabulin with 75 mgm(-2) docetaxel (35/75 mgm(-2);13 patients) and 30 mgm(-2) ombrabulin with 100 mgm(-2) docetaxel (30/100 mgm(-2);16 patients). Dose-limiting toxicities were grade 3 fatigue (two patients;42/75, 35/100), grade 3 neutropaenic infection (25/75), grade 3 headache (42/75), grade 4 febrile neutropaenia (30/100), and grade 3 thrombosis (35/ 100). Toxicities were consistent with each agent;mild nausea/vomiting, asthaenia/fatigue, alopecia, and anaemia were common, as were neutropaenia and leukopaenia. Diarrhoea, nail disorders and neurological symptoms were frequent at 100 mgm(-2) docetaxel. Pharmacokinetic analyses did not show any relevant drug interactions. Ten patients had partial responses (seven at 30 mgm(-2) ombrabulin), eight lasting > 3 months. Conclusions: Sequential administration of ombrabulin with 75 or 100 mgm(-2) docetaxel every 3 weeks is feasible.

关键词： docetaxel ombrabulin pharmacokinetics vascular disrupting agent

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