个体化医疗的现状与未来生物标志物（PPT） .ppt

个体化医疗的现状与未来四 生物标志物研究 吕林莉m d ph d 东南大学医学院 outline 生物标志物的概念如何评价生物标志物 生物标志物的研究方法 生物标志物的概念 什么是生物标志物 biomarker measurableandquantifiablebiologicalparameters amedicalsubjectheading mesh term 1989 acharacteristicthatisobjectivelymeasuredandevaluatedasanindicatorofnormalbiologicalprocesses pathogenicprocessesorpharmacologicalresponsestoatherapeuticintervention biomarkerdefinitionsworkinggroup 2001 nih featuresofausefulbiomarker highsensitivityandspecificityeasyaccessiblesamplecorrelationwithhistologicalscoringchangeinadvanceofclinicalsignstranslationalfromresearchtoclinicaluse 不同水平生物标志物 dna primarytranscript mrna transcription protein translation rnaprocessing nucleus biomarkerexamples cholesterolisoneofthemostwell knownbiomarkersofcardiovascularhealthphysicalmeasurements bodytemperature fever bloodpressure strokerisk otherbiomarkers bloodsugarlevel diabetes antigens hepatitis proteins heartattack geneticvariations huntington sdisease 生物标志物的临床应用 ludwigjaetal naturereviews2005 5 845 856 目前临床很多疾病的诊断依赖病理诊断 但不能作为常规筛查 监测手段众多疾病缺乏早期 特异性生物标志物治疗缺乏个体化方案 生物标志物应用现状 clinjamsocnephrol3 1895 1901 2008 biomarkersforchronickidneydisease arewetreatingsub populations fromkalow tyndale meyer pharmacogenomics 2001 novelbiomarkersareneeded early accuratediagnosis individualizedtherapyandimprovedtreatmentoutcomesbetterdefinedpopulationswillallowmorespecificdrugs betterefficacy fewersideeffects theuseofbiomarkerswillchangemedicalpracticefromapopulation basedapproachtoanindividualizedapproach felixfrueh associatedirectorofgenomicsatcder fda evolutionofthebiomarkersresearch highplasmacholesterolandcardiovasculardiseases nearly50percentofallfuturemyocardialinfarctionandstrokeeventsoccurinthosewithnormalorbelownormallipidlevels euroaspirestudygroup 1997 ofmi additionalbiomarkers inflammation hs crpandcardiovascularrisk hs crpisthemostwidelystudiedbiomarkerofinflammationincardiovascularrisk sincetheearly1990swiththedevelopmentofhighlysensitiveassaysforitsmeasurement correlationsofhs crpwithbothcardiovascularriskfactorsandfuturecardiovasculareventshasbeenpossible crpandldl clevelsandtheriskofcardiovasculardiseases increasedcrplevelsareassociatedwithincreasedriskofcardiovasculareventsindependentlyofldl clevels ridkerpmetal 2002 27 939women highcrp highldl highcrp lowldl lowcrp lowldl lowcrp highldl porbabilityofevent freesurvival yearsoffollow up 0 99 0 98 0 97 0 96 0 00 1 00 0 2 4 6 8 evolutionofthebiomarkersresearch crpandldl clevelsandevent freesurvivalamongwomen 27 939womenthemedianvalueswereasfollows c reactiveprotein 1 52mg lldlcholesterol 123 7mg dlor 3 20mmol l crpandldl ccouldgivebetterprognosticinformationthanthetwomarkersseparately ridkerpmetal 2002 如何评价生物标志物 常用评价指标 一 敏感性 二 特异性 三 youden指数 四 阳性似然比 五 阴性似然比 六 阳性预报值 七 阴性预报值 八 roc曲线 ecg诊断试验的结果 一 敏感性 sensitivity tp tp fn tpr truepositiverate trp sen 416 416 104 0 8该指标只与病例组有关 反映了诊断试验检出病例的能力 ecg诊断试验的结果 二 特异性 specificity spe truenegativerate tnr tn fp tn 171 171 9 0 95该指标只与对照组有关 反映了诊断试验排除非病例的能力 灵敏度与特异度的优缺点 优点 灵敏度与特异度不受患病率的影响 其取值范围均在 0 1 之间 其值越接近于1 说明其诊断准确性越好 缺点 当比较两个诊断试验时 单独使用灵敏度或特异度 可能出现矛盾 解决办法 将两指标结合 youden指数 阳性似然比 阴性似然比等 ecg诊断试验的结果 三 youden指数 sen spe 1 tpr fpr 0 8 0 05 0 75youden指数取值范围在 0 1 之间 其值越接近1 诊断准确性越好 ecg诊断试验的结果 ecg诊断试验的结果 医生最关心的问题 1 试验阳性时患病的概率多大 2 试验阴性时不患病的概率多大 阳性预测值是在诊断试验阳性的受试者中 标准诊断有病的病例 真阳性 所占的比例 阴性预测值则是在诊断试验为阴性的受试者中 标准诊断证实无病的受试者 真阴性 所占的比例 阳性预报值与阴性预报值 roc曲线 roc receiveroperatingcharacteristic的缩写 译为 接受者工作特征 roc曲线研究历史1950 s雷达信号观测能力评价1960 s中期实验心理学 心理物理学1970 s末与1980 s初诊断医学 roc的涵义与起源 不同诊断界值时灵敏度与特异度间的平衡 tradeoff 0 20 40 60 80 100 50 60 70 80 90 100 特异度 灵敏度 百分率 receiveroperatingcharacteristiccurveareaundercurve auc graphed curve1 50 purechance nobetterthanrandomguesscurve3isbetterthancurve2curve4 1 0 totallysensitive completelyaccurateclassificationofeffectivelyandless effectivelyinstructedstudents 完美与无用的roc曲线 真阳性率即灵敏度 假阳性率即1 特异度 机率线 chanceline diagonalreferenceline 诊断准确度较低 0 7 0 0 0 2 0 4 0 6 0 8 1 0 0 0 0 2 0 4 0 6 0 8 1 0 fpr t p r a 0 664 a 0 830 诊断准确度较高 0 9 0 0 0 2 0 4 0 6 0 8 1 0 0 0 0 2 0 4 0 6 0 8 1 0 fpr t p r a 0 938 roc曲线下面积 area 与诊断准确度高低高0 90 1 00 excellent a 中0 80 0 90 good b 0 70 0 80 fair c 低0 60 0 70 poor d 0 50 0 60 fail f roc曲线小结 roc曲线反映了灵敏度与特异度间的平衡 增加灵敏度将降低特异度 增加特异度将降低灵敏度 在roc曲线空间 如果曲线沿着左边线 然后沿着上边线越紧密 则试验准确度越高 在roc曲线空间 如果曲线沿着机会线 45度对角线 越紧密 则试验准确度越低 roc曲线下面积是重要的试验准确度指标 生物标志物研究方法 vasanrs circulation 2006 113 2335 2362 theagendiamammaprinttest首个fda批准的基因组检测试验 feb 2007 howtheygotthere 2002 discoveryof70genesignature 117patients 2002 duplicationofresults inanothersampleset 295patients 2006 assayperformance2006 optimizedarrayformat reproducibility backtooriginalsampleset2006 externalconfirmation 307patients 5hospitals 2007 approvalbyfda 生物标志物研究技术 传统研究方法 pcr westernblotting elisa etal新型研究方法 基因组学技术蛋白质组学技术 2 dige ms 蛋白质芯片 生物标志物研究方法 question1 whathumansamplesshouldbecollected andhowshouldtheybeused doesthisvarybetweendiscovery validationandimplementation answer1 allbiologicalsamplesareeligibleforcollectioncollectedbiologicalmaterialdependsonanalyteandtissuesourceexamples biologicalfluids serum plasma urine csf secretions saliva seminalfluid bodycavityfluids pleuralfluid peritonealfluid etc specifictissuematerial specializedcells reproductivecells non cellular ideal biomarkerdiscoverysamplesshouldbeidenticaltotheprojectedtestingsituation e g donotstudyplasmafordiscovery andthenvalidateorimplementassayusingserum practical setupstudywithsamplesthatareasclosetothetestingsituationaspossible question2 whatistheroleofroutinelyaccessiblebiofluidssuchasplasma serum andurine whatistheroleof proximal fluidslikecsf synovialfluid ascites pancreaticductalfluid etc whatistheroleofsolidtissues roleofroutinelyaccessiblebiofluids veryimportantinthediscoveryofbiomarkersofdiseases systemicvs organspecific local importantfor earlydetection diseaseseverity tumorburden prognosis monitoringofresponsetotherapy proximalfluids canreflectdiseaseperturbationsintheorgansortissuesfromwhichtheyaresecretedsolidtissues veryimportantforthede