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Comparison of Four Methods for Handing Missing Data in Longitudinal Data Analysis through a Simulation Study

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Open Journal of Statistics 2014年第11期4卷 933-944页

作者： Xiaoping Zhu Biostatistics & Data Management Regeneron Pharmaceuticals Inc. Basking Ridge USA

Missing data can frequently occur in a longitudinal data analysis. In the literature, many methods have been proposed to handle such an issue. Complete case (CC), mean substitution (MS), last observation carried forward (LOCF), and multiple imputation (MI) are the four most frequently used methods in practice. In a real-world data analysis, the missing data can be MCAR, MAR, or MNAR depending on the reasons that lead to data missing. In this paper, simulations under various situations (including missing mechanisms, missing rates, and slope sizes) were conducted to evaluate the performance of the four methods considered using bias, RMSE, and 95% coverage probability as evaluation criteria. The results showed that LOCF has the largest bias and the poorest 95% coverage probability in most cases under both MAR and MCAR missing mechanisms. Hence, LOCF should not be used in a longitudinal data analysis. Under MCAR missing mechanism, CC and MI method are performed equally well. Under MAR missing mechanism, MI has the smallest bias, smallest RMSE, and best 95% coverage probability. Therefore, CC or MI method is the appropriate method to be used under MCAR while MI method is a more reliable and a better grounded statistical method to be used under MAR.

关键词： MCAR MAR Complete Case Mean Substitution LOCF Multiple Imputation

Challenges in Preclinical Toxicology Assessment for Immune odulators

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Challenges in Preclinical Toxicology Assessment for Immune o...

NOTUM inhibition increases endocortical bone formation and bone strength

中国毒理学会第七次全国毒理学大会暨第八届湖北科技论坛

作者： Matt Yu Liu Toxicology Drug Safety and PharmacometricsRegeneron PharmaceuticalsInc.

T-cells have an important role in antiviral and anti-tumor immune *** the chronic infection or tumor microenvironment,the immune system is held in check by inhibitory receptors and *** dysfunctional T-cells render the immune system unable to eliminate infections and *** advances in understanding the mechanism of various immune checkpoints,such as CTLA-4,PD-1,PD-Ll,have led to development and approvals of several monoclonal antibodies for cancer *** encouraging clinical data from the immune modulators intensifies our interest in exploring additional therapeutics targeting various T-cells checkpoint *** toxicology evaluations of those immune checkpoint inhibitors present a unique challenge in which we have to consider and dissect the desired pharmacology related immune response and the exaggerated toxicity observed from enhanced immunologic *** presentation will review the current advancement of the cancer immune modulators and use case studies to illustrate the challenges in preclinical toxicology assessment of immune modulators.

关键词： immune modulators T-cells checkpoints PD-1

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Bone Research 2019年第1期7卷 54-65页

作者： Robert Brommage Jeff Liu Peter Voge Faika Mseeh Andrea Y.Thompson David G.Potter Melanie K.Shadoan Gwenn M.Hansen Sabrina Jeter-Jones Jie Cui Dawn Bright Jennifer P.Bardenhagen Deon D.Doree Sofia Moverare-Skrtic Karin H.Nilsson Petra Henning Ulf H.Lerner Claes Ohlsson Arthur T.Sands James E.Tarver David R.Powell Brian Zambrowicz Qingyun Liu Lexicon pharmaceuticals The WoodlandsTXUSA Wntrix HoustonTXUSA PRA Health Sciences RaleighNCUSA University of Pennsylvania PhiladelphiaPAUSA regeneron pharmaceuticals TarrytownNYUSA University of Texas HoustonTXUSA Centre for Bone and Arthritis Research Institute of MedicineThe Sahlgrenska Academy at University of GothenburgGothenburgSweden Centre for Bone and Arthritis Research University of GothenburgGothenburgSweden Biogen CambridgeMAUSA St.Jude Children’s Research Hospital MemphisTNUSA MD Anderson Cancer Center HoustonTXUSA Bethyl Laboratories MontgomeryTXUSA Merck RahwayNJUSA Nurix San FranciscoCAUSA

The disability,mortality and costs caused by non-vertebral osteoporotic fractures are *** osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral *** bone is a major determinant of non-vertebral bone *** identify novel osteoporosis drug targets,we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable *** bone thickness was substantially elevated in Notum?/?*** is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not *** orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were *** increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone ***,inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

关键词： disability osteoporosis fractures

STING-ing Pain:How Can Pro-inflammatory Signaling Attenuate Pain?

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Neuroscience Bulletin 2021年第7期37卷 1075-1078页

作者： Wolfgang Liedtke Department of Neurology Duke University School of MedicineDurhamNC 27710USA Department of Anesthesiology Duke University School of MedicineDurhamNC 27710USA Department of Neurobiology Duke University School of MedicineDurhamNC 27710USA Duke Neurology Clinics for Headache Head-Pain and Trigeminal Sensory DisordersDurhamNC 27705USA Clinics for Innovative Pain Therapy Department of AnesthesiologyDuke UniversityRaleighNC 27512USA Chair of Neurology Global Scientific Development CouncilRegeneron PharmaceuticalsTarrytownNY 10591USA

Inflammation typically induces pain by producing pro-inflammatory mediators,but increasing evidence also indicates a role for inflammation in the resolution of pain by inducing anti-inflammatory and pro-resolution med... 详细信息

关键词： inflammatory interferon rigorous

REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters

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四川生理科学杂志 2021年第1期43卷 118-118页

作者： Alina Baum regeneron pharmaceuticals Inc. Tarrytown NY 10591 USA. Southwest National Primate Research Center Texas Biomedical Research Institute San Antonio TX 78245 USA. BIOQUAL Rockville MD 20850 USA.

An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019(COVID-19)is *** previously described REGN-COV2,a cocktail of two potent neutralizing antibodies(REGN10987 and REGN10933)that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike *** this report,we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques,which may model mild disease,and golden hamsters,which may model more severe *** demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques.

关键词： REG antibodies acute

阿柏西普玻璃体腔注射和光动力疗法治疗中国新生血管性老年性黄斑变性患者的疗效对比:SIGHT研究

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中华眼底病杂志 2019年第2期35卷 156-165页

作者：黎晓新陈有信张军军许迅张风 ChuiMing Gernmy Cheung RuiYu HusainKazmi OlafSowade OliverZeitz on behalf of the SIGHT study group 北京大学人民医院眼科视觉损失与修复教育部重点实验室 100044 中国医学科学院北京协和医学院北京协和医院眼科 100730 四川大学华西医院眼科成都610041 上海交通大学附属第一人民医院眼科 200080 首都医科大学附属北京同仁医院北京同仁眼科中心北京市眼科学与视觉科学重点实验室 100730 Department of Ophthalmology Singapore Eye Research InstituteSingapore Department of Ophthalmology Bayer USWhippanyNewYork Ophthalmology Regeneron PharmaceuticalsInc.TarrytownNewYork Development PharmaceuticalsBayer AGBerlinGermany

目的对比观察玻璃体注射阿柏西普(IAI)和光动力疗法(PDT)治疗中国继发于新生血管性老年性黄斑变性(nAMD)的经典为主型脉络膜新生血管(CNV)患者的安全性和有效性。方法随机、双盲、多中心为期52周(2011年12月至2014年8月)的Ⅲ期临床研究... 详细信息

目的对比观察玻璃体注射阿柏西普(IAI)和光动力疗法(PDT)治疗中国继发于新生血管性老年性黄斑变性(nAMD)的经典为主型脉络膜新生血管(CNV)患者的安全性和有效性。方法随机、双盲、多中心为期52周(2011年12月至2014年8月)的Ⅲ期临床研究。研究注册码NCT01482910。入组患者按照3:1比例随机分为IAI组、PDT→IAI组。IAI组患者在基线和第4、8、16、24、32、40、48周时接受2 mg IAI治疗,第28、36周时分别接受假注射治疗。PDT→IAI组患者在基线时均强制接受1次PDT治疗,第12、24周时若满足PDT再治疗条件,则再次予以PDT治疗;基线和第4、8、16、24周时接受假注射治疗,第28、32、36、40、48周时接受2 mg IAI治疗。报告的主要有效性结果为第28周时平均BCVA相较基线的变化和第52周时的结果。安全性评价包括发生治疗相关不良事件(TEAEs)患者百分比。结果入组304例患者中,IAI组、PDT→IAI组分别为228、76例。第28周时,IAI组、PDT→IAI组患者平均BCVA较基线变化值分别为+14.0、+3.9个字母;第52周时,两组患者BCVA较基线变化值分别为+15.2、+8.9个字母,差异为+6.2个字母(95% CI 2.6~9.9,P=0.000 9)。第52周时,两组患者平均中心凹视网膜厚度分别下降?189.6、?170.0 μm。IAI组中BCVA提高最为显著者为年龄<65岁、活动性CNV面积<总病灶面积50%者。IAI组、PDT→IAI组患者眼部最常见TEAEs为黄斑纤维化[11.8%(27/228)、6.6%(5/76)]、BCVA下降[6.6%(15/228)、21.1%(16/76)]。抗血小板研究合作组定义的动脉血栓栓塞事件3例,但均被认为与药物无关。结论中国nAMD患者阿柏西普治疗效果优于PDT。阿柏西普疗效在全部患者中均可持续至第52周。不良事件的发生率与已知的阿柏西普安全性数据一致。

关键词：湿性黄斑变性囱物疗法脉络膜新生血管化/药物疗法血管生成抑制剂/治疗应用抗体,单克隆/治疗应用光化学疗法

Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma

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四川生理科学杂志 2021年第10期43卷 1816-1816页

作者： Leonard B Bacharier From Monroe Carell Jr. Children's Hospital at Vanderbilt Nashville (L.B.B.) Fundación CIDEA Buenos Aires (J.F.M.) Campbelltown Hospital Campbelltown NSW and Western Sydney University Sydney (C.H.K.) - both in Australia Bambino Gesù Children's Hospital IRCCS Rome (A.G.F.) Clinique Spécialisée en Allergie de la Capitale Quebec QC Canada (R.G.) Hospital Vall d'Hebron Barcelona (I.M.) Arizona Allergy and Immunology Research Gilbert (N.J.) Peninsula Research Associates Rolling Hills Estates CA (L.D.S.) Sanofi Bridgewater NJ (X.M. U.K. P.J.R. E.L.) Sanofi Beijing (D.L.) regeneron pharmaceuticals Tarrytown NY (Y.Z. F.A.K. Y.D. M.R. D.M.W. G.D.Y. N.A. D.J.L.) Sanofi Chilly-Mazarin France (A.H.K. L.P.M.) and Sanofi Genzyme Cambridge MA (N.P. M.H.).

Background:Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standardof-care *** monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory ***:In this 52-week phase 3,randomized,double-blind,placebo-controlled trial,we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab(at a dose of 100 mg for those weighing≤30 kg and 200 mg for those weighing>30 kg)or matched placebo every 2 *** the children continued to receive a stable dose of standard background *** primary end point was the annualized rate of severe asthma *** end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second(ppFEV1)at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered(ACQ-7-IA)at week *** points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype(≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of≥20 ppb at baseline)or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline.

关键词： millimeter cubic continued

Dupilumab in Adults and Adolescents with Eosinophilic Esophagitis

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四川生理科学杂志 2022年第12期44卷 2116-2116页

作者： Evan S Dellon From the Center for Esophageal Diseases and Swallowing University of North Carolina School of Medicine Chapel Hill (E.S.D.) Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine Cincinnati (M.E.R. M.H.C.) Northwestern University Feinberg School of Medicine Chicago (I.H.) Mount Sinai Center for Eosinophilic Disorders Icahn School of Medicine at Mount Sinai New York (M.C.) and Regeneron Pharmaceuticals Tarrytown (X.S. M.P.K. M.A.K. J.D.H. B.B. E.M. B.A. N.A. W.K.L. M.F.W. M.R. D.R.W. G.D.Y. B.S. J.M. A.G. A.S.) - both in New York Amsterdam University Medical Center Amsterdam (A.J.B.) Hospital General de Tomelloso Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas Madrid and Instituto de Investigación Sanitaria de Castilla-La Mancha Toledo - both in Spain (A.J.L.) Children's Hospital of Philadelphia Philadelphia (J.M.S.) University of California San Diego La Jolla and Rady Children's Hospital San Diego - both in California (S.A.) Sanofi Bridgewater NJ (K.P. E.L.) Sanofi Chilly-Mazarin France (L.P.M.) and Sanofi Cambridge MA (N.P.).

Background:Dupilumab,a fully human monoclonal antibody,blocks interleukin-4 and interleukin-13 signaling,which have key roles in eosinophilic ***:We conducted a three-part,phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo(Part A)or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo(Part B)up to week 24.

关键词： monoclonal placebo weekly

Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome

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四川生理科学杂志 2023年第10期45卷 1848-1848页

作者： Gregory G Schwartz From the Division of Cardiology University of Colorado School of Medicine Aurora (G.G.S.) Assistance Publique–Hôpitaux de Paris Hôpital Bichat Paris Diderot University Sorbonne Paris Cité FACT (French Alliance for Cardiovascular Trials) and INSERM Unité 1148 (P.G.S.) and Sanofi (C.H. G.L.) — all in Paris the National Heart and Lung Institute Imperial College Royal Brompton Hospital London (P.G.S.) the State University of New York Downstate School of Public Health Brooklyn (M.S.) and Regeneron Pharmaceuticals Tarrytown (R.P. W.J.S.) — both in New York Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School Boston (D.L.B.) the Division of Cardiovascular Disease University of Alabama at Birmingham Birmingham (V.A.B.) Estudios Cardiológicos Latinoamérica Instituto Cardiovascular de Rosario Rosario Argentina (R.D.) Sanofi Bridgewater NJ (J.M.E. A.M. J.-F.T.) the Canadian VIGOUR Centre University of Alberta Edmonton and St. Michael’s Hospital University of Toronto Toronto — both in Canada (S.G.G.) Stanford Center for Clinical Research Department of Medicine Stanford University Stanford CA (R.A.H. K.W.M.) the Department of Cardiology Leiden University Medical Center Leiden the Netherlands (J.W.J.) Duke Clinical Research Institute Duke University Medical Center (K.Q. M.T.R. P.T.) and the Division of Cardiology Department of Medicine Duke University School of Medicine (M.T.R.) Durham NC Green Lane Cardiovascular Services Auckland City Hospital Auckland New Zealand (H.D.W.) and the Department of Medicine III Goethe University Frankfurt am Main Germany (A.M.Z.).

Background:Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular *** sought to determine whether alirocumab,a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9(PCSK9),would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.

关键词： cardiovascular acute coronary