个体化医疗的现状与未来生物标志物（PPT） .ppt

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1、 个体化医疗的现状与未来个体化医疗的现状与未来四四.生物标志物研究生物标志物研究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？生物标志物的概念生物标志物的概念什么是生物标志物什么是生物标志物(biomarker)？“measurable and quantifiable biological parameters”-a Medical Subject Heading(MeSH)term,1989“A characteristic that is objectively measured and evaluated as an indicator of normal

2、 biological processes,pathogenic processes or pharmacological responses to a therapeutic intervention.”-Biomarker Definitions Working Group,2001,NIHFeatures of a Useful BiomarkernHigh sensitivity and specificitynEasy accessible samplenCorrelation with histological scoringnChange in advance of clinic

3、al signsnTranslational from research to clinical use 不同水平生物标志物不同水平生物标志物DNAPrimary transcriptmRNATranscriptionproteinTranslationRNA processingNucleusBiomarker Examples Cholesterol is one of the most well-known biomarkers of cardiovascular health Physical measurements:body temperature(fever);blood pre

4、ssure(stroke risk)Other biomarkers:blood sugar level(diabetes)antigens(hepatitis)proteins(heart attack)genetic variations(Huntingtons disease)生物标志物的临床应用生物标志物的临床应用Ludwig JA et al.Nature reviews 2005,5:845-856 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生物标志物应用现状Clin J Am Soc

5、Nephrol 3:18951901,2008.Biomarkers for chronic kidney diseaseAre we treating sub-populations?疾病疾病药物药物无反应率无反应率抑郁SSRIs,SNRIs,TCAs40-60%哮喘-adrenergics,LTD44-75%糖尿病Sulfonylurea,Biguanides,Glitazones50-75%肿瘤(乳腺癌 肺癌)Various70-100%From Kalow,Tyndale&Meyer,Pharmacogenomics,2001Novel biomarkers are needednEa

6、rly,accurate diagnosis -Individualized therapy and improved treatment outcomesnBetter defined populations will allow more specific drugs-Better efficacy-Fewer side effects“The use of biomarkers will change medical practice from a population-based approach to an individualized approach”Felix Frueh,As

7、sociate Director of Genomics at CDER,FDAEvolution of the biomarkers researchHigh plasma cholesterol and cardiovascular diseasesElevated plasma cholesterol Centre Moderate+severe Severe Italy 57.8%(93/161)19.3%(31/161)France 48.8%(189/387)17.3%(67/387)Nearly 50 percent of all future myocardial infarc

8、tion and stroke events occur in those with normal or below normal lipid levels.EUROASPIRE Study Group,1997Additional biomarkers(inflammation)Hs-CRP and cardiovascular risk Hs-CRP is the most widely studied biomarker of inflammation in cardiovascular risk.Since the early 1990s with the development of

9、 highly sensitive assays for its measurement,correlations of hs-CRP with both cardiovascular risk factors and future cardiovascular events has been possible.CRP and LDLC levels and the risk of cardiovascular diseasesC-Reactive Protein(mg/L)3.0 160LDL-cholesterol(mg/dL)3.02.01.00.0Multivariable Relat

10、ive RiskIncreased CRP levels are associated with increased risk of cardiovascular events independently of LDL-C levelsRidker PM et al.,200227,939 womenHigh CRP-high LDLHigh CRP-low LDLLow CRP-low LDLLow CRP-high LDLPorbability of Event-free SurvivalYears of Follow-up0.990.980.970.960.001.0002468Evol

11、ution of the biomarkers research:CRP and LDL-C levels and event-free survival among women27,939 womenThe median values were as follows:C-reactive protein:1.52 mg/L LDL cholesterol:123.7 mg/dL or:3.20 mmol/L CRP and LDL-C could give better prognostic information than the two markers separately.Ridker

12、 PM et al.,2002如何评价生物标志物？如何评价生物标志物？常用评价指标常用评价指标（一）敏感性（一）敏感性（二）特异性（二）特异性（三）（三）Youden指数指数（四）阳性似然比（四）阳性似然比（五）阴性似然比（五）阴性似然比（六）阳性预报值（六）阳性预报值（七）阴性预报值（七）阴性预报值（八）（八）ROC曲线曲线ECG诊断试验的结果ECG诊断结果心肌梗塞合 计出现不出现阳 性阴 性合计416(TP)9（FP）425104(FN)171（TN）275520180700(N)一、敏感性（一、敏感性（Sensitivity):TP/(TP+FN)=TPR(true positive r

13、ate)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ECG诊断结果心肌梗塞合 计出现不出现阳 性阴 性合计416(TP)9（FP）425104(FN)171（TN）275520180700(N)二、特异性（二、特异性（Specificity)Spe=True negative rate(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。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

14、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ECG诊断结果心肌梗塞合 计出现不出现阳 性阴 性合计416(TP)9（FP）425104(FN)171（TN）275520180700(N)三、三、Youden指数，指数，=Sen+Spe-1=TPR-FPR =0.8-0.05=0.75Youden指数取值范围在（指数取值范围在（0，1）之间，其值越接近）之间，其值越接近1，诊断准

15、确性越好。，诊断准确性越好。ECG诊断试验的结果ECG诊断结果心肌梗塞合 计出现不出现阳 性阴 性合计416(TP)9（FP）425104(FN)171（TN）275520180700(N)ECG诊断试验的结果ECG诊断结果心肌梗塞合 计出现不出现阳 性阴 性合计416(TP)9（FP）425104(FN)171（TN）275520180700(N)医生最关心的问题：医生最关心的问题：1.试验阳性时患病的概率多大？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？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（真阳阳性预测值是在诊断试验阳性的受试者

16、中，标准诊断有病的病例（真阳性）所占的比例性）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。（真阴性）所占的比例。ECG诊断结果心肌梗塞合 计出现不出现阳 性阴 性合计416(TP)9（FP）425104(FN)171（TN）275520180700(N)阳性预报值与阴性预报值ROC曲线 ROCROC（receiver operating receiver operating characteristiccharacteristic的缩写，译为的缩写，译为“接受者工接受者工作特征作特征”）ROCROC曲线研究历史曲线研究历史1950s 雷达信号观测能力评价雷达信号观测能力评价1960s中期中期 实验心理学、心理物理学实验心理学、心理物理学1970s末与末与1980s初初 诊断医学诊断医学ROC的涵义与起源的涵义与起源不同诊断界值时不同诊断界值时灵敏度与特异度间的平衡灵敏度与特异度间的平衡(trade off)(trade off)0204060801005060708