1、908欢迎关注本刊公众号中国癌症杂志2023年第33卷第10期 CHINA ONCOLOGY 2023 Vol.33 No.10论 著CDK4/6抑制剂不良反应评估:基于FAERS数据库的真实世界研究 佘友俊1,郭子寒1,张忠伟2,杜琼11.复旦大学附属肿瘤医院药剂科,复旦大学上海医学院肿瘤学系,上海 200032;2.复旦大学附属肿瘤医院重症医学科,复旦大学上海医学院肿瘤学系,上海 200032摘要 背景与目的:细胞周期蛋白依赖性激酶4和6(cyclin-dependentkinase4/6,CDK4/6)抑制剂的开发和批准是激素受体阳性转移性乳腺癌治疗的一个重要里程碑。这类药物疗效相似,但
2、不良事件(adverseevents,AE)各有不同,直接影响临床用药选择。目前关于CDK4/6抑制剂的安全性在真实世界中的系统研究尚不全面。而本研究则通过对美国食品药品管理局(FoodAndDrugAdministration,FDA)不良事件报告系统(FDAAdverseEventReportingSystem,FAERS)进行信号挖掘,比较CDK4/6抑制剂AE的差异,发现未知AE信息,旨在为临床治疗方案的选择和AE监测提供参考依据。方法:提取FAERS数据库中2014年第一季度至2023年第一季度的所有数据,去除重复报告后,对将“palbociclib(哌柏西利)”、“abemacic
3、lib(阿贝西利)”和“ribociclib(瑞波西利)”列为“首要怀疑”的报告,通过比例失衡测量法进行数据分析。本研究采用报告比值比(reporting odds ratio,ROR)法和MHRA法识别信号,阳性信号需要同时满足:报告数3、ROR的95%置信区间的下限、比例报告比值比(proportional reporting ratios,PRR)2、24的标准。结果:研究选出85 562条与CDK4/6抑制剂相关的AE报告。哌柏西利在血液学和淋巴系统AE中信号最强(白细胞减少症ROR=20.01)。在胃肠道系统和肝肾系统中,哌柏西利的AE信号较其他药物低(腹泻ROR=1.95,-谷氨酰
4、转移酶升高ROR=0.36,血肌酐升高ROR=1.01)。阿贝西利在胃肠道系统信号最强(腹泻ROR=13.54);在肝肾系统也表现出较强的AE信号(-谷氨酰转移酶升高ROR=2.58,血肌酐升高ROR=7.74);在血液和淋巴系统AE信号较其他药物低(白细胞减少ROR=5.34)。瑞波西利在血液和淋巴系统中的AE信号强度低于哌柏西利(白细胞减少症ROR=7.55);但在肝肾系统AE中,瑞波西利的-谷氨酰转移酶升高信号强度最高(ROR=4.05)。另外,在罕见严重的肝脏AE中,阿贝西利肝衰竭(ROR=3.50)和药物诱导的肝损伤(ROR=4.68)信号最强。研究还发现多形性红斑(ROR=3.06
5、)是阿贝西利新的AE信号。结论:CDK4/6抑制剂安全性的特点各不相同。对FAERS数据库的分析揭示哌柏西利和瑞波西利有血液和淋巴系统毒性、阿贝西利存在胃肠道毒性和肝毒性。研究同时发现阿贝西利严重AE为多形性红斑。结果提示,治疗期间医疗人员需要依据患者生理状态和药物AE的特点进行个体化用药选择和AE监测。关键词 CDK4/6抑制剂;不良事件;FAERS;真实世界;比例失衡法;药物警戒中图分类号:R730.51文献标志码:ADOI:10.19401/ki.1007-3639.2023.10.003Evaluation of adverse events of CDK4/6 inhibitors:
6、a real-world study based on the FAERS database SHE Youjun1,GUOZihan1,ZHANGZhongwei2,DU Qiong1(1.DepartmentofPharmacy,FudanUniversityShanghaiCancerCenter,DepartmentofOncology,ShanghaiMedicalCollege,FudanUniversity,Shanghai200032,China;2.DepartmentofCriticalCare,FudanUniversityShanghaiCancerCenter,Dep
7、artmentofOncology,ShanghaiMedicalCollege,FudanUniversity,Shanghai200032,China)Correspondenceto:DUQiong,E-mail:dujoan-.Abstract Background and purpose:Thedevelopmentandapprovalofinhibitorsofcyclin-dependentkinase4/6(CDK4/6)isanessentialmilestoneintreatinghormonereceptor-positivemetastaticbreastcancer
8、.Theefficacyofthesedrugsissimilar,buttheadverseevents(AE)aredifferent,directlyaffectingthephysicianschoiceofdrug.Thereisnosystematicstudyonthesafetyof基金项目:上海市抗癌协会“翱翔计划”项目(SHAX-QT-202101)。作者简介:佘友俊(ORCID:0000-0001-9616-7005),药学硕士,初级药师。通信作者:杜琼(ORCID:0000-0003-4830-9704),药学硕士,主管药师,E-mail:dujoan-。909中国癌症
9、杂志2023年第33卷第10期CDK4/6inhibitorsintherealworld.Inthisstudy,wecomparedthedifferencesinAEofCDK4/6inhibitorsthroughsignalminingintheFDAAdverseEventReportingSystem(FAERS)andidentifiedunknownAEsignalstoprovideareferencefortheclinicalchoiceof treatment and monitoring AE.Methods:AlldataintheFAERSdatabasewer
10、eextractedfromthefirstquarterof2004tothefirstquarterof2023.Afterremovingduplicates,datawereanalyzedbythedisproportionalitymethodforreportsrankingpalbociclib,abemaciclib,orribociclibastheprimarysuspect.Signalswereidentifiedusingthereportingoddsratio(ROR)andMHRAmethods.Positivesignalswererequiredtomee
11、tthefollowingcriteria:thenumberofreports3,thelowerlimitofthe95%confidenceintervaloftheROR1,proportionalreportingratios(PRR)2,andthe2 4.Results:A total of 85 562 reports of AE associated withCDK4/6inhibitorswereidentified.ThehighestsignalintensityofpalbociclibwasobservedinhematologicandlymphaticAE(le
12、ukopeniaROR=20.01).PalbociclibhadlowerAEsignalsinthegastrointestinal,hepatic,andrenalsystemsthantheotherdrugs(diarrheaROR=1.95,gamma-glutamyltransferaseincreasedROR=0.36,bloodcreatinineincreasedROR=1.01).Abemaciclibhadthestrongestsignalinthegastrointestinalsystem(diarrheaROR=13.54);italsoshowedastro
13、ngAEsignalinthehepaticandrenalsystems(gamma-glutamyltransferaseincreasedROR=2.58,bloodcreatinineincreasedROR=7.74)andalowerAEsignalthantheotherdrugsinthebloodandlymphaticsystems(leukopeniaROR=5.34).RibociclibhadalowerAEsignalintensityinthebloodandlymphaticsystemthanpalbociclib(leukopeniaROR=7.55);ho
14、wever,amonghepaticAE,ribociclibhadthehighestsignalintensityofincreasedgamma-glutamyltransferase(ROR=4.05).InrareseverehepaticsystemicAE,abemaciclibhadthestrongestsignalinhepaticfailure(ROR=3.50)anddrug-inducedliverinjury(ROR=4.68).Erythemamultiformewasanewlyidentifiedsignalintheabemaciclibreports(RO
15、R=3.06).Conclusion:ThesafetyprofileofCDK4/6inhibitorsvaries.AnalysisoftheFAERSdatabaserevealedhematologicandlymphaticsystemtoxicitiesforpalbociclibandribociclibandgastrointestinalandhepatorenaltoxicitiesforabemaciclib.ErythemamultiformewasfoundasanovelsevereAEforabemaciclib.Individualizeddrugselecti
16、onandmonitoringofAEbasedonthepatientsphysiologicalstatusandAEareneededduringtreatment.Key words CDK4/6inhibitors;Adverseevents;FAERS;Realworld;Disproportionalityanalysis;Pharmacovigilance乳腺癌是女性最常见的恶性肿瘤,以激素受体(hormonereceptor,HR)阳性、人表皮生长因子受体2(humanepidermalgrowthfactor receptor 2,HER2)阴性乳腺癌最为常见,大约占全部乳
17、腺癌的70%1。内分泌治疗是早期HR+/HER2-乳腺癌的有效治疗手段。然而对于晚期患者,单纯使用内分泌治疗药物已不足以控制癌症进展1。细胞周期蛋白依赖性激酶4和6(cyclin-dependentkinase 4/6,CDK4/6)抑制剂分子靶向药物的应用改变了HR+/HER2-晚期乳腺癌的临床治疗模式,患者的生存也获得了突破性的改 善2。哌柏西利是第一个进入临床的CDK4/6抑制剂,瑞波西利和阿贝西利紧随其后。中国自主研发的CDK4/6抑制剂达尔西利也于2022年上市。CDK4/6抑制剂中,哌柏西利、瑞波西利、阿贝西利和达尔西利已被国内外指南推荐用于HR+/HER2-乳腺癌女性患者的治疗3
18、-4。这类药物耐受性良好,疗效相似,但在不良反的类型和发生频率方面存在一定差异5-8。在进行药物选择时,医疗团队需要系统了解CDK4/6抑制剂不良事件(adverseevents,AE)的异同,在发挥疗效的同时尽可能减轻AE对患者治疗连续性和生活质量产生的影响。目前,CDK4/6抑制剂AE的管理主要参考临床试验结果9-10。然而受限于受试者严格的入组标准和有限的随访时间,发生率较低的严重AE可能无法在临床试验中充分体现。CDK4/6抑制剂AE的对比研究主要是基于临床试验数据的meta分析,对于真实世界安全性数据的系统研究仍处于初步阶段5,11-13。美国食品药品管理局(FoodAnd Drug
19、Administration,FDA)不良事件报告系统(FDA AdverseEventReportingSystem,FAERS)是一个涵盖数千万例药物AE报告的自发报告系统,包括了FDA收集的所有不良事件信息和用药错误信息,为AE的早期识别提供庞大的真实世界数据来源。与PubMed、EMBASE、MEDLINE数据库收录的药品AE相关文献不同,FAERS数据库中的AE信息是以单个病例为单位进行记录及查询,数据更为原始。同时FAERS数据库包含所有美国上市药物的用药详细信息,拥有更广泛的用910佘友俊,等 CDK4/6抑制剂不良反应评估:基于FAERS数据库的真实世界研究药人群数据。通过对F
20、AERS中的AE信号进行挖掘,可以及时对临床研发期间未识别的安全信号进行持续的风险管理14。本研究通过对FAERS数据库中CDK4/6抑制剂的相关报告开展数据挖掘,了解真实世界中不同CDK4/6抑制剂AE的异同,探索发现未知的AE和罕见的严重AE信号,从而为CDK4/6抑制剂的选择和长期应用管理提供参考依据。1 资料和方法1.1 数据来源本研究的数据来自FAERS数据库。研究提取2014年第一季度到2023年第一季度的ASC数据包的全部信息。所有数据导入到SAS 9.4软件中,按照FDA推荐的去除重复报告方法进行数据清理并开展分析15。数据筛选依据FAERS数据库中字段中的“DRUGNAME”
21、进行,筛选“palbociclib”、“abemaciclib”和“ribociclib”的报告,并将报告的怀疑程度限定为“首要怀疑(primarysuspect)”。截至2023年7月20日,达尔西利(dalpiciclib)在FAERS数据库无不良事件报告,故本研究未对达尔西利开展数据挖掘与分析。1.2 AE信号检测与分析FAERS数据库是根据国际医学用语词典监管活动医学词典(MedicalDictionaryforRegulatoryActivities,MedDRA)中的首选术语(preferred term,PT)进行描述的。PT术语可以归属于3个层级,其中最高层级为系统器官分类(s
22、ystemorganclassification,SOC)。FAERS数据库中AE信号的检测通常使用比例失衡测量法(disproportionalityanalysis,DPA),通过比较指定药物与所有其他药物之间发生AE的比例,从而识别AE的信号16。研究采用报告比值比(reporting odds ratio,ROR)法和综合标准法(MedicinesandHealthcareProductsRegulatoryAgency,MHRA)对CDK4/6抑制剂的AE信号进行检测,具体计算方法见表117。MHRA法参考比例报告比值比(proportional reporting ratio,PR
23、R)、2以及报告数3个指标对AE信号进行评价。为避免假阳性信号的出现,阳性AE信号的判断应同时满足ROR法阳性:ROR的95%置信区间(95%confidenceinterval,95%CI)的下限(ROR025)和MHRA法阳性:报告数3、PRR2、24。ROR值越大表示信号越强,说明药物与AE的相关性越强。CDK4/6抑制剂报告中罕见严重AE的筛选是依据欧盟发布的指定医疗事件(designatedmedicalevent,DME)清 单18进行。表1 CDK4/6抑制剂及AE的2X2列联表及比例失衡的计算框架Tab.1 Two-by-two contingency table for co
24、mbinations of CDK4/6 inhibitors and AE and the framework for calculating disproportionalityTargetAE(orPT)OtherAETotal CDK4/6inhibitorsaca+cOtherdrugsbdb+dTotala+bc+da+b+c+dROR=(a/b)/(c/d);95%CI=eln(ROR)1.96(1/a+1/b+1/c+1/d)0.5;PRR=(a/a+c)/(b/b+d),2=(O-E2/E),(O=a,E=a+ba+c/a+b+c+d).AE:Adverseevents;PT
25、:Preferredterm;2:Chi-square.2 结果2.1 CDK4/6抑制剂AE报告的人口统计学信息本研究通过图1所示的数据处理流程,2014年1月2023年3月共计筛选出85 562条与CDK4/6抑制剂相关的AE报告,人口统计学信息见表2。在这些报告中,哌柏西利报告AE数目最多,其次是瑞波西利,阿贝西利报告AE数量最少。超过半数报告的患者年龄在60岁以上。从报告来源来看,消费者自主报告占比最高(41.98%),其次是药师(26.62%),医师(15.12%)次之。来自中国的报告占数据库的极少部分(0.92%)。严重AE报告占据43.29%,主要临床结局是住院(15.11%)和
26、死亡(13.33%)。AE的中位开始时间:阿贝西利瑞波西利哌柏西利。911中国癌症杂志2023年第33卷第10期表2 FAERS数据库中CDK4/6抑制剂相关报告的人口统计学信息Tab.2 Population characteristics of CDK4/6 inhibitor-related reports in the FAERS databaseItemPalbociclibAbemaciclibRibociclibNumberofreports66 2507 57311 739Gender n(%)Female 61977(93.55)6775(89.46)10823(92.2)M
27、ale 1521(2.30)130(1.72)234(1.99)Missing 2752(4.15)668(8.82)682(5.81)Medianage(Q1,Q3)66(57,74)64(56,72)61(51,71)Year of report n(%)Before 201930432(45.94)2346(30.98)3140(26.75)20209951(15.02)1522(20.10)1962(16.71)20218909(13.45)1368(18.06)2255(19.21)202212852(19.40)1850(24.43)3202(27.28)20234106(6.20
28、)487(6.43)1180(10.05)Reporter n(%)Consumer28344(42.78)3355(44.30)6021(51.29)Pharmacist19203(28.99)1850(24.43)1724(14.69)Physician8867(13.38)1098(14.50)2970(25.30)Others9836(14.85)1270(16.77)1024(8.73)Countryn(%)China542(0.81)176(2.32)66(0.56)Unknown 2473(3.74)743(9.81)238(2.03)Others63777(96.21)6830
29、(90.20)11501(97.97)Typeofreports Non-serious35561(53.68)4108(54.25)8855(75.43)Serious30689(46.32)3465(45.75)2884(24.57)Outcome Life-threatening347(0.52)106(1.40)359(3.06)Hospitalization8708(13.14)1612(21.29)2608(22.22)Disability178(0.27)42(0.55)89(0.76)Death8250(12.45)664(8.77)2489(21.20)Others48767
30、(73.62)5149(67.99)6194(52.76)Medianofonsettime(Q1,Q3)79(20,276)32(11,102)63(16,253)图1 FAERS数据库中CDK4/6抑制剂相关报告的筛选和分析流程Fig.1 Flowchart for screening and data analysis of reports related to CDK4/6 inhibitors in the FAERS databaseAll records from FAERS(n=19514140)Duplicaterecords(n=3220786)Report after d
31、e-duplication(n=16293354)Forreportswiththesamecasenumber,selectthemostrecentFDADT.ForthosecaseswiththesamecasenumberandFDADT,scleetthereportwiththehigherISRnumber.Screeningwasbasedonthedrugnames:palbociclib,abemaciclib,andribociclib,whilelimitingthereportedlevelofsuspiciontoPrimarySuspectDisproporti
32、onalityanalysisandsignaldetectionofallAEsusingtheRORmethodcombinedwiththeMHRAmethodScreening for rare signals of seriousadversereactionsonthebasisoftheEUDesignatedMedicalEvent(DME)listPalbociclib(n=66250)PositivePTsignals(n=308)DME signals(n=2)Abemaciclib(n=7573)PositivePTsignals(n=159)DME signals(n
33、=6)Ribociclib(n=11739)PositivePTsignals(n=452)DME signals(n=1)912佘友俊,等 CDK4/6抑制剂不良反应评估:基于FAERS数据库的真实世界研究2.2 CDK4/6抑制剂AE信号在各系统器官中的分布将AE信号按SOC进行分类,三种CDK4/6抑制剂的报告数量、信号强度及分布情况见图2。哌柏西利在全身性疾病及给药部位各种反应的报告最多(N=38 045),血液及淋巴系统疾病信号最强(ROR=2.79)。阿贝西利在胃肠系统疾病的报告最多(N=4 106)且信号最强(ROR=3.86)。瑞波西利在全身性疾病及给药部位各种反应的报告最多(
34、N=8 917),在良性、恶性及性质不明的肿瘤的信号最强(ROR=4.59)。图2 CDK4/6抑制剂AE在不同系统器官中的分布情况Fig.2 Distribution of AE of CDK4/6 inhibitorin different systemic organsNPTrepresentedthenumberofPTsthatgenerateasignalundertheRORcombinedwithMHRAmethod;ROR025representedthelowerlimitofthe95%confidenceintervalofROR.General disorders a
35、nd administration site conditionsGastrointestinalInvestigationsSkinandsubcutaneoustissuedisordersNervoussystemdisordersNeoplasmsbenign,malignantandunspecified(inclcystsandpolyps)Respiratory,thoracicandmediastinaldisordersInjury,poisoningandproceduralcomplicationsMusculoskeletalandconnectivetissuedis
36、ordersInfections and infestationsBloodandlymphaticsystemdisordersPsychiatricdisordersMetabolismandnutritiondisordersVasculardisordersEyedisordersRenalandurinarydisordersCardiac disordersHepatobiliarydisordersImmunesystemdisordersEarandlabyrinthdisordersReproductivesystemandbreastdisordersEndocrine d
37、isorders1140762291817178920443410332170914349413112061327714112000021241172413592117181722912875121441181380452732427912136751368910883111991245510380925490035803485435902648182614361236133312377491682841410616057297785248824643276386762197202971113092043714939349891756716094309728823948290819252517
38、20672239149212618996576751042825656132376651.121.642.561.260.782.421.170.640.970.942.790.491.090.810.710.460.260.670.691.390.550.411.213.862.260.910.632.191.280.360.480.973.070.362.570.940.551.170.572.810.360.640.711.411.131.422.421.210.724.591.310.441.020.923.050.601.230.890.790.740.811.971.470.691
39、.430.94Systemorganclassification(SOC)PalbociclibNegativesignal0ROR0251Positivesignal1ROR025NPTNPTNPTNNNRORRORRORAbemaciclibRibociclib2.3 CDK4/6抑制剂AE信号在PT层级的分析研究对所有信号在PT层级进行分析,将出现频率最高的前30个信号检测结果见表3。死亡、与恶性肿瘤相关的AE、COVID-19等相关PT不纳入分析。研究在哌柏西利报告中发现听觉减退、免疫系统紊乱、淋巴水肿、指甲折断或改变等新AE信号。在阿贝西利报告中发现上腹痛、口腔黏膜炎等新AE信号。在
40、瑞波西利报告中发现免疫反应降低、胸腔积液等新AE信号。CDK4/6抑制剂在重点器官中常见的AE信号检测结果见图36。哌柏西利和瑞波西利在血液和淋巴系统的信号强度较高。哌柏西利在白细胞减少症(ROR=20.01)和红细胞减少症(ROR=13.84)中信号最强。而阿贝西利在胃肠道和营养系统中具有更高的信号强度,以腹泻(ROR=13.54)的信号最强。在肝肾系统AE中,瑞波西利和阿贝西利均有较高肝功能相关信号。瑞波西利在丙氨酸氨基转移酶升高的信号最强(ROR=3.70)。阿贝西利在血肌酐升高下的信号强度最高(ROR=7.74)。在全身性AE中,哌柏西利的疲乏的信号强度最高(ROR=4.59)。913
41、中国癌症杂志2023年第33卷第10期表3 CDK4/6抑制剂的信号检测中出现频率最高的前30个AETab.3 Top 30 adverse events with the highest frequency of occurrence in signaling assays for CDK4/6 inhibitorsNo.PalbociclibAbemaciclibRibociclibPreferredterm(PT)nRORPreferredterm(PT)nRORPreferredterm(PT)nROR1Fatigue11 3914.59Diarrhoea2 02713.54Nause
42、a1 2781.982Alopecia4 8487.28Nausea5692.70Fatigue1 2592.033Neutropenia3 4608.29Fatigue5092.51Neutropenia8758.564Decreased appetite2 5443.12Vomiting4023.24Vomiting7702.025Plateletcountdecreased1 6434.58Decreased appetite2814.36Whitebloodcellcountdecreased7208.216Hotflush*1 3235.61Dehydration2546.86Dia
43、rrhoea6811.337Haemoglobin decreased1 1453.15Whitebloodcellcountdecreased2267.80Pain6291.208Epistaxis1 0073.84Neutropenia1704.99Malaise5761.529Bone pain8424.13Anaemia1693.18Dyspnoea5661.2010Leukopenia7844.67Weightdecreased1592.09Asthenia5081.6311Oral pain6187.92Alopecia1532.81Alopecia4963.0012Hypoacu
44、sis*6183.81Abdominalpainupper*1472.68Rash4751.2913Laboratorytestabnormal3823.81Blood creatinine increased1427.74Decreased appetite4552.3014Blood test abnormal3698.43Abdominal pain1402.21Pruritus4311.4415Lacrimation increased3203.43Interstitiallungdisease1199.58Cough4301.9416Taste disorder3046.40Cons
45、tipation1192.14Constipation3752.2217Myelosuppression2955.38Plateletcountdecreased1073.73Pyrexia3701.2818Immunesystemdisorder*2465.65Myelosuppression10223.51Back pain3511.7919Cytopenia2297.54Drugintolerance863.62Paininextremity3501.3720Lymphoedema*2079.40Haemoglobin decreased852.95Anaemia3362.0721Ony
46、choclasis*1998.79Pulmonaryembolism832.99Decreasedimmuneresponsiveness*30145.5622Nail disorder*1877.38Hepaticfunctionabnormal798.29Feeling abnormal*2861.3423Musculoskeletalchestpain*1853.36Pneumonitis7511.24Electrocardiogram QT prolonged2849.5724Pulmonarythrombosis1393.85Thrombosis672.96Haemoglobin d
47、ecreased2673.0425Oralmucosalblistering1356.06Thrombocytopenia662.21Weightdecreased2651.1426Gingivalpain1194.33Neutrophilcountdecreased626.10Neutrophilcountdecreased2588.4027Nasaldryness964.51Redbloodcellcountdecreased597.60Peripheralswelling2502.1028Whitebloodcelldisorder9310.15Fullbloodcountdecreas
48、ed5510.71Pleuraleffusion*2464.7429Appetite disorder924.51Renal impairment542.44Leukopenia2425.9730Redcelldistributionwidthincreased*876.73Stomatitis*503.15Plateletcountdecreased2382.72 *:AEnotmentionedinFDAdruglabels.914佘友俊,等 CDK4/6抑制剂不良反应评估:基于FAERS数据库的真实世界研究图3 CDK4/6抑制剂的血液和淋巴系统AE信号检测Fig.3 Signal de
49、tection of hematologic and lymphatic AEs of CDK4/6 inhibitorsAEAbemaciclibPalbociclibRibociclibAbemaciclibPalbociclibRibociclibAbemaciclibPalbociclibRibociclibAbemaciclibPalbociclibRibociclibAbemaciclibPalbociclibRibociclibAbemaciclibPalbociclibRibociclibLeukopeniaMyelosuppressionErythropeniaLymphop
50、eniaAnaemiaNeutropenia6.04(5.34,6.84)20.01(19.59,20.43)7.55(7.08,8.05)6.28(5.48,7.20)7.29(7.03,7.55)2.35(2.07,2.66)7.60(5.88,9.82)13.84(13.09,14.64)5.57(4.70,6.61)0.47(0.18,1.25)0.82(0.67,1.01)3.41(2.76,4.20)3.09(2.73,3.50)2.24(2.15,2.33)2.35(2.17,2.55)5.27(4.63,6.00)9.43(9.16,9.70)8.58(8.09,9.11)25