Department of Epidemiology Public Health College of Harbin Medical University 哈尔滨医科大学流行病学教研室 Department of epidemiology ， Harbin Medical University

Department of Epidemiology Public Health College of Harbin Medical University Stage of susceptibility Subclinical Disease Stage of Clinical Disease Stage of Recovery, Disability, or Death Exposure PathologicalChanges Onset of Symptoms Usual Time of Diagnosis 疾病自然史（ Natural History of Disease ）

Department of Epidemiology Public Health College of Harbin Medical University 目 录 目 录  概述  筛检试验的评价  筛检效果的评价  Introduction  Evaluation of screening test  Evaluation of effectiveness Outline

Department of Epidemiology Public Health College of Harbin Medical University  筛检是运用快速、简便的 试验、检查或其他方法， 将健康人群中那些可能有 病或缺陷，但表面健康的 人、同那些可能无病者鉴 别开来 Screening is defined as the use of quick and simple testing procedures to identify and separate persons who are apparently well, but who may be at risk of a disease, from those who probably do not have the disease. 第一节 概述 Introduction

Department of Epidemiology Public Health College of Harbin Medical University Apparently Well Population to be Tested Screening Test Diagnostic Test Disease or Risk Factor Present Disease or Risk Factor Absent Negatives (Normal) (Persons presumed to be free of disease) Negative on screening Positive on screen, no disease Positive on screen, disease present Positives (abnormal) presumed to have disease Treatment Intervention 筛检试验流程图 Flow diagram of screening test

Department of Epidemiology Public Health College of Harbin Medical University 筛查方法的评价与选择程序 Procedures of evaluation and selection for screening test 金标准 (gold standard) 目标人 群 Target populatio n 病人 Patien t 非病 人 Non- patien t 待评价筛查方法 Screening to be evaluated 评价指标 Evaluation indicator ＋ － ＋ －

Department of Epidemiology Public Health College of Harbin Medical University 筛检试验 Screening test 识别健康人群中未被发现的某病患者 或可疑患者，或高危个体 Screening is the detection of patients, suspected patient and high risk of the disease in healthy population

Department of Epidemiology Public Health College of Harbin Medical University 筛检试验 Screening test 问卷、常规体格检查、物理学检查、 实验室检验、分子生物学技术 Questionnaire, routine physical examination, physical examination, laboratory tests, molecular biology techniques

Department of Epidemiology Public Health College of Harbin Medical University 根据所用的筛检方法的数 量多少  单项筛检  多项筛选 筛检的分类 Categories of screening Based on the on the quantity of screening methods Single screening Multiple screening

Department of Epidemiology Public Health College of Harbin Medical University 根据筛检对象的范围不同  人群筛检  目标筛检 筛检的分类 Categories of screening Based on the scope of screening subjects Mass screening Targeted screening

Department of Epidemiology Public Health College of Harbin Medical University 简单性 廉价性 快速性 安全性 可接受性 筛检试验应具备五个特征 Five characteristics that screening test should have Simple Cheap Quick Safe Acceptable

Department of Epidemiology Public Health College of Harbin Medical University 一级预防 二级预防 疾病的自然史 流行病学检测 筛检的目的 Primary prevention Secondary prevention Natural history of disease Epidemiological surveillance Purposes of screening

Department of Epidemiology Public Health College of Harbin Medical University  筛检的疾病是当地一个 重大的公共卫生问题  具备有效的治疗或预防 方法 应用筛检的原则 Principles for the application of screening The disease being screened should be a major problem Acceptable treatment or prevention methods should be available for individuals with diseases discovered in the screening process.

Department of Epidemiology Public Health College of Harbin Medical University  有进一步确诊的方法 与条件  该病的自然史明确 A suitable and effective test or examination for the disease should be available The natural history of the disease should be adequately understood 应用筛检的原则 Principles for the application of screening

Department of Epidemiology Public Health College of Harbin Medical University  该病具有较长的潜伏期 或领先时间  预期有良好的筛检效益 The disease should have a recognizable course, with early and latent states of the disease being identifiable Expected good efficiency of screening should be available 应用筛检的原则 Principles for the application of screening

Department of Epidemiology Public Health College of Harbin Medical University 伦理学问题 Ethical Issues 尊重个人意愿 Respect for person’s will 有益无害 Useful and harmless 公正 Fairness

Department of Epidemiology Public Health College of Harbin Medical University 一、筛检试验的评价方法 （ Evaluation methods ）  确定金标准 (Determine Gold Standard)  选择研究对象 (Chose Study Subjects)  样本量的估计 (Estimate Sample Size)  整理评价结果 (Sort out evaluation result) 第二节 筛检试验的评价 Evaluation of Screening test

Department of Epidemiology Public Health College of Harbin Medical University 金 标 准金 标 准 所谓 “ 金标准 ” 是指当前 临床医学界公认的诊断 疾病的最可靠方法 Gold Standard The best available test that is universally recognized by clinical medical circles is called the GOLD STANDARD.

Department of Epidemiology Public Health College of Harbin Medical University 病例组 纳入各种类型的病人 对照组 最好选择需要与研究疾病鉴别 的其他病人，即所选择的对照 组与病例组具有许多相似的条 件 研究对象 Study Subjects Case group Include appropriate spectrum of patients Control group Need to be distinguished to the disease studied, that is the control has co-morbid conditions with case

Department of Epidemiology Public Health College of Harbin Medical University 样 本 量 Sample Size 影响样本量的因素 待评价筛检试验的灵敏度 待评价筛检试验的特异度 显著性水平（ α ） 允许误差（ d ） Factors determine sample size Sensitivity of screening to be evaluated Specificity of screening to be evaluated Significance level （ α ） Allowable error （ d ）

Department of Epidemiology Public Health College of Harbin Medical University 当待评价筛检试验的灵敏度和特异度均接近 50 ％ Both sensitivity and specificity of screening to be evaluated approach 50% n: the number of abnormal (diseased) or normal (healthy) patients in the study. δ: admissible error. P: the estimation of sensitivity and specificity for testing. u a : the u value for the cumulative probability equal to a/2.

Department of Epidemiology Public Health College of Harbin Medical University 当待评价筛检试验的灵敏度和特异度小于 20% 或大于 80% Both sensitivity and specificity of screening to be evaluated less than 20% or greater than 80%

Department of Epidemiology Public Health College of Harbin Medical University 本来有病，被筛检为阳性 本来有病，被筛检为阴性 本来无病，被筛检为阳性 本来无病，被筛检为阴性 评价结果 Evaluation Results

Department of Epidemiology Public Health College of Harbin Medical University 评价结果 Evaluation Results Disease Status ( Gold Standard ) +- Test Result + Have disease, test positive a (TP) Free of disease, test positive b (FP) Test Positive - Have disease, test negative c (FN) Free of disease, test negative d (TN) Test Negative Have disease Free of disease

Department of Epidemiology Public Health College of Harbin Medical University  真实性（ validity ）  可靠性（ reliability ）  预测值（ predictive value ） 二、筛检试验的评价指标 Evaluation Index

Department of Epidemiology Public Health College of Harbin Medical University  灵敏度（ sensitivity ）  假阴性率（ false negative rate ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N 真实性（ validity ）

Department of Epidemiology Public Health College of Harbin Medical University False Negative Rate Likelihood of a negative result when patient actually has disease False Negatives Sensitivity

Department of Epidemiology Public Health College of Harbin Medical University False Negatives Sensitivity Likelihood of a negative result when patient actually has disease False Negative Rate

Department of Epidemiology Public Health College of Harbin Medical University False negative rate increases with decreased sensitivity Sensitivity False Negatives False Negative Rate Likelihood of a negative result when patient actually has disease

Department of Epidemiology Public Health College of Harbin Medical University  特异度（ specificity ）  假阳性率（ false positive rate ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N 真实性（ validity ）

Department of Epidemiology Public Health College of Harbin Medical University False Positive Rate Likelihood of a positive result when patient does not have the disease False Positives Specificity

Department of Epidemiology Public Health College of Harbin Medical University False Positive Rate Likelihood of a positive result when patient does not have the disease False Positives Specificity

Department of Epidemiology Public Health College of Harbin Medical University False Positive Rate Likelihood of a positive result when patient does not have the disease False positive rate increases with decreased specificity Specificity False Positives

Department of Epidemiology Public Health College of Harbin Medical University  正确指数（ Youden’s index ） ＝（特异度＋灵敏度）－ 1 ＝ 1 －（假阳性率＋假阴性率） 真实性（ validity ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N

Department of Epidemiology Public Health College of Harbin Medical University  阳性似然比 (positive likelihood ratio ，＋ LR ）  阴性似然比 (negative likelihood ratio ，－ LR ） 真实性（ validity ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N

Department of Epidemiology Public Health College of Harbin Medical University 真实性（ validity ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N  一致率（ agreement rate ），符合率 一致率

Department of Epidemiology Public Health College of Harbin Medical University 真实性（ validity ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N 取值范围： -1 和＋ 1 之间 Range: between -1 and +1 Kappa 值判断标准 Kappa 值一致性强度 ＜0＜0 弱 0 ～ 0.2 轻 0.21 ～ 0.40 尚好 0.41 ～ 0.60 中度 0.61 ～ 0.80 高度 0.81 ～ 1 最强

Department of Epidemiology Public Health College of Harbin Medical University Kappa 值 = 实际一致性 / 非机遇一致性 观察一致性 (Observation consistency) 机遇一致性 (Opportunity consistency) 非机遇一致性 (Non-opportunity consistency) 实际一致性 (Actral consistency) 真实性（ validity ） 筛检试验 (screening) 金标准 (gold standard) 合计 (total) 患者 (patient) 非患者 (non-patient) 阳性 (positive) 真阳性 (TP) A 假阳性 (FP) B R1R1 阴性 (negative) 假阴性 (FN) C 真阴性 (TN) D R2R2 合计 (total) C1C1 C2C2 N

Department of Epidemiology Public Health College of Harbin Medical University  标准差与变异系数 coefficient of variance ， CV  符合率（ agreement rate ） Agreement rate Screening test 2 Screening test 1 Total PositiveNegative Positive ABR1R1 Negative CDR2R2 Total C1C1 C2C2 N 可靠性（ reliability ）

Department of Epidemiology Public Health College of Harbin Medical University 影响可靠性的因素 Determinants of reliability ☉ Biological variations of subjects ☉ Variations in different observers ☉ Variations in different lab condition  受试对象生物学变异  观察变异  实验室条件

Department of Epidemiology Public Health College of Harbin Medical University  阳性预测值 ( positive predictive value )  阴性预测值 (negative predictive value) Screening test Gold standard Total PatientNon-patient PositiveTrue Positive AFalse Positive BR1R1 Negative False Negative CTrue Negative DR2R2 TotalC1C1 C2C2 N 预测值（ predictive value ）

Department of Epidemiology Public Health College of Harbin Medical University 灵敏度、特异度、患病率与预测值的关系 Relationship between sensitivity, specificity, prevalence and predict value

Department of Epidemiology Public Health College of Harbin Medical University sensitivity and specificity in different blood sugar level blood sugar SN SP blood sugar SN SP （ mg/100ml ） （﹪） （﹪） （ mg/100ml ） （﹪） （ ﹪） Relationship between sensitivity and specificity 灵敏度与特异度的关系

Department of Epidemiology Public Health College of Harbin Medical University 非病人病人 某项诊断标准的数值 截断点 Threshold 三、筛检试验截断值的确定 Determination of screening cut-off point 理想情况 Ideal situation 理想情况 Ideal situation 人数 Number NormalDisease

Department of Epidemiology Public Health College of Harbin Medical University 非病人 Normal 病人 Abnormal 某项诊断标准的数值 Cut-off 三、筛检试验截断值的确定 Determination of screening cut-off point 实际情况 Actual situation 实际情况 Actual situation 人数 Population

Department of Epidemiology Public Health College of Harbin Medical University Number of persons Measurement Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal) NormalAbnormal a c b d Normal a c d b

Department of Epidemiology Public Health College of Harbin Medical University Number Measurement Where cut-off is placed determines sensitivity and specificity Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)

Department of Epidemiology Public Health College of Harbin Medical University Number Measurement Where cut-off is placed determines sensitivity and specificity Normal Abnormal Few False Negatives High Sensitivity - result + result Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)

Department of Epidemiology Public Health College of Harbin Medical University Number Measurement Where cut-off is placed determines sensitivity and specificity Normal Abnormal Few False Positives High Specificity - result + result Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)

Department of Epidemiology Public Health College of Harbin Medical University Number Measurement Where cut-off is placed determines sensitivity and specificity Normal Abnormal Trade off between False – and False + - result + result Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)

Department of Epidemiology Public Health College of Harbin Medical University Number Measurement Test with High Sensitivity Normal Abnormal A negative result allows you to rule-out whatever you are testing - result + result SnNout Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)

Department of Epidemiology Public Health College of Harbin Medical University Number Measurement Test with High Specificity Normal Abnormal A positive result allows you to rule-in whatever you are testing - result + result SpPin Screening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)

Department of Epidemiology Public Health College of Harbin Medical University 用真阳性率和假阳性率作图得出的曲线，可用于 确定筛检试验的截断值。 A receiver operating characteristic (ROC), or simply ROC curve, is a graphical is a graphical plot of the sensitivity, or true positives, vs. (1 − specificity), or false positives, for a binary classifier system as its discrimination threshold is varied. 受试者工作特性曲线 Receiver operator characteristic curve, ROC

Department of Epidemiology Public Health College of Harbin Medical University 特异度 血糖测定诊断糖尿病的 ROC 曲线 截断点 Cutoff point ROC curve for diagnosis of diabetes using blood glucose

Department of Epidemiology Public Health College of Harbin Medical University 第三节 筛检效果评价 Evaluation of effectiveness 一、收益  选择患病率高的人群  选用高灵敏度的筛检试验  采用联合试验  串联  并联 Yield  To select the population with high prevalence rate  To select the test with high sensitivity  To design a combine test  Series test  Parallel test

Department of Epidemiology Public Health College of Harbin Medical University 二、筛检的生物学效果评价 Biological effectiveness evaluation 病死率、死亡率、生存率 筛检组 Screened group 未筛检组 Unscreened group 比较 Fatality rate 、 mortality rate 、 survival rate

Department of Epidemiology Public Health College of Harbin Medical University 三、筛检的卫生经济学效果评价 Health-economic effectiveness evaluation  成本效果分析 Cost-effectiveness analysis  成本效益分析 Cost-benefit analysis  成本效用分析 Cost-utility analysis

Department of Epidemiology Public Health College of Harbin Medical University  领先时间偏倚  病程长短偏倚  志愿者偏倚 Lead time bias Length bias Volunteer bias 第四节 筛检中的偏倚及其控制 Bias and Control

Department of Epidemiology Public Health College of Harbin Medical University  领先时间偏倚 （ lead time bias ） 领先时间：筛检诊断时间和临床诊断时间之差 Lead time: Interval between the diagnosis of a disease at screening and the usual time of diagnosis (by symptoms) Diagnosis by screening Diagnosis via symptoms Lead Time

Department of Epidemiology Public Health College of Harbin Medical University  Assumes survival is time between screen and death  Does not take into account lead time between diagnosis at screening and usual diagnosis. Diagnosis by screening in 1994 Death in 2008 Survival = 14 years  认为延长的生存时间是筛检诊断时间与死亡时间之差  没有考虑筛检诊断时间和临床诊断时间之间的领先时间  领先时间偏倚 （ lead time bias ）

Department of Epidemiology Public Health College of Harbin Medical University Diagnosis by screening in 1994 Usual time of diagnosis via symptoms in 1998 Lead Time 4 years Death in 2008 True Survival = 10 years Survival = 14 years  领先时间偏倚 （ lead time bias ）

Department of Epidemiology Public Health College of Harbin Medical University  病程长短偏倚 （ length bias ） 疾病 开始 筛检 查出 症状 开始 死亡 ODPY O Biological onset of disease Y Symptoms Begin D Death P Disease detectable via screening

Department of Epidemiology Public Health College of Harbin Medical University 筛检 Screening ODPY ODPY ODPY ODPY ODPY OPYD 时间 Time 恶性程度高 Aggressive 恶性程度低 Less aggressive  病程长短偏倚 （ length bias ）

Department of Epidemiology Public Health College of Harbin Medical University  志愿者（ volunteer bias ） Type of bias where those who choose to participate are likely to be different from those who don’t. 筛检参加者与不参加者之间，某些特征可能存在不同 而导致的偏倚。