流行病學第七章篩檢

1、 第七章 篩檢ScreeningStage of susceptibilityStage of Subclinical DiseaseStage of Clinical Disease Stage of Recovery,Disability, or DeathExposurePathological ChangesOnset ofSymptomsUsual Time of Diagnosis疾病自然史（Natural History of Disease）疾病自然史與篩檢Natural History of Disease and Screening開始暴露出現(xiàn)癥狀臨床前可檢查期 疾病發(fā)生診

2、斷治療 如果疾病在臨床前期出現(xiàn)一些可以識別的異常特征，如腫瘤的早期標識物（biomarkers）、血壓升高、血脂升高等，則可使用一種或多種方法將其查出，并對其做進一步的診斷和治療，則可延緩疾病的發(fā)展，改善其預后 引 言易感期 臨床前期 臨床期 殘疾、死亡 康 復Pathological Changes開始暴露出現(xiàn)癥狀臨床前可檢查期 疾病發(fā)生診斷治療篩檢Screening 引 言康 復殘疾、死亡 易感期 臨床前期 臨床期 疾病自然史與篩檢Natural History of Disease and Screening目 錄 概述 篩檢試驗的評價 篩檢效果的評價Introduction Evalu

3、ation of screening testEvaluation of effectivenessOutline篩檢是運用快速、簡便的試驗、檢查或其他方法，將健康人群中那些可能有病或缺陷，但表面健康的人、同那些可能無病者鑒別開來 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 pro

4、bably do not have the disease.第一節(jié) 概述Introduction根據(jù)所用的篩檢方法的數(shù)量多少單項篩檢多項篩選篩檢的分類Categories of screeningBased on the on the quantity of screening methodsSingle screening Multiple screening根據(jù)篩檢對象的范圍不同整群篩檢 選擇性篩檢篩檢的分類Categories of screeningBased on the scope of screening subjects Mass screening Selective scr

5、eening篩檢試驗Screening test 是用于識別外表健康的人群中可能患有某疾病的個體或未來發(fā)病危險性高的個體的方法。Screening is the detection of patients, suspected patient and high risk of the disease in healthy population .篩檢試驗Screening test 問卷、常規(guī)體格檢查、物理學檢查、實驗室檢驗、分子生物學技術Questionnaire, routine physical examination, physical examination, laboratory

6、tests, molecular biology techniques 簡單性 廉價性 快速性 安全性 可接受性篩檢試驗應具備五個特征Five characteristics that screening test should have Simple Cheap Quick Safe Acceptable二級預防一級預防疾病的自然史 篩檢的目的Secondary prevention Primary prevention Natural history of disease Purposes of screening診斷試驗是指應用實驗、儀器設備等手段對疾病進行診斷的一切檢測方法。 Diag

7、nostic test is to distinguish diseased from the non-diseased but suspected to have disease. 診斷試驗Diagnostic test包括各種實驗室檢查、影像診斷、儀器檢查，還包括病史詢問、體格檢查等。Laboratory tests, imaging diagnosis, Instrumental test， history report and physical examinationApparently Well Population to be TestedScreening TestDiagnos

8、tic TestDisease or Risk Factor PresentDisease or Risk Factor AbsentNegatives (Normal) (Persons presumed to be free of disease)Negative on screeningPositive on screen, no disease Positive on screen, disease presentPositives (abnormal)presumed tohave diseaseTreatment Intervention篩檢試驗流程圖 Flow diagram o

9、f screening test篩檢試驗與診斷試驗的區(qū)別Distinguish between screening test and diagnostic test篩檢試驗Screening test診斷試驗Diagnostic test對象健康人或無癥狀的病人病人目的發(fā)現(xiàn)可疑病人對病人進行確診要求快速、簡便、安全，高靈敏度 復雜、準確性和特異度高 費用經(jīng)濟、廉價花費較高 處理用診斷試驗確診 嚴密觀察和及時治療 第一節(jié) 概 述篩檢的疾病是當?shù)匾粋€重大的公共衛(wèi)生問題具備有效的治療或預防方法應用篩檢的原則 Principles for the application of screeningThe

10、 disease being screened should be a major problemAcceptable treatment or prevention methods should be available for individuals with diseases discovered in the screening process有進一步確診的方法與條件該病的自然史明確A suitable and effective test or examination for the disease should be available The natural history of

11、 the disease should be adequately understood應用篩檢的原則 Principles for the application of screening該病具有較長的潛伏期或領先時間預期有良好的篩檢效益The disease should have a recognizable course, with early and latent states of the disease being identifiableExpected good efficiency of screening should be available應用篩檢的原則 Princi

12、ples for the application of screening 篩檢方法 Good screening test 確診方法 Appropriate diagnostic method 有效的治療手段 Effective treatment 三者缺一不可，否則將導致衛(wèi)生資源浪費，給篩檢試驗陽性者帶來生理和心理上的傷害等不良后果第一節(jié) 概 述 基本條件Basic criteria for a successful screening program倫理學問題Ethical Issues 尊重個人意愿 Respect for persons will 有益無害 Useful and ha

13、rmless 公正 Fairness第二節(jié) 篩檢試驗的評價Evaluation of Screening test 篩檢試驗的評價就是將待評價的篩檢試驗與診斷目標疾病的標準方法即“金標準”(gold standard)進行同步盲法（blinding）比較，判定該方法對疾病“診斷”的真實性和價值。 篩查方法的評價與選擇程序 Procedures of evaluation and selection for screening test 金標準 (gold standard)目標人群Targetpopulation病人Patient非病人Non-patient待評價篩查方法Screening t

14、o be evaluated評價指標Evaluation indicator一、篩檢試驗的評價方法 （Evaluation methods）確定金標準 (Determine Gold Standard)選擇研究對象 (Chose Study Subjects)樣本量的估計 (Estimate Sample Size) 整理評價結果 (Sort out evaluation result)第二節(jié) 篩檢試驗的評價Evaluation of Screening test金 標 準所謂“金標準”是指當前臨床醫(yī)學界公認的診斷疾病的最可靠方法Gold StandardThe best available

15、test that is universally recognized by clinical medical circles is called the GOLD STANDARD . 病例組 納入各種類型的病人 對照組 最好選擇需要與研究疾病鑒別的其他病人，即所選擇的對照組與病例組具有許多相似的條件研究對象 Study Subjects Case group Include appropriate spectrum of patients Control group Need to be distinguished to the disease studied, that is the c

16、ontrol has co-morbid conditions with case樣 本 量 Sample Size 影響樣本量的因素待評價篩檢試驗的靈敏度待評價篩檢試驗的特異度顯著性水平（）允許誤差（） Factors determine sample sizeSensitivity of screening to be evaluated Specificity of screening to be evaluated Significance level（）Allowable error（）當待評價篩檢試驗的靈敏度和特異度均接近50Both sensitivity and specifi

17、city of screening to be evaluated approach 50%n: the number of abnormal (diseased) or normal (healthy) patients in the study.: admissible error. P: the estimation of sensitivity and specificity for testing. ua : the u value for the cumulative probability equal to a/2. 當待評價篩檢試驗的靈敏度和特異度小于20%或大于80%Both

18、 sensitivity and specificity of screening to be evaluated less than 20% or greater than 80% 待評價的篩檢試驗的估計靈敏度為75%，特異度55%，計算病例和對照組的樣本量設 = 0.05， = 0.08，則：n1 = (1.96/0.08)2(1-0.75)0.75=112.5113n2 = (1.96/0.08)2(1-0.55)0.55=148.6149評價該試驗，病例組為113例，對照組為149例第二節(jié) 篩檢試驗的評價本來有病，被篩檢為陽性本來有病，被篩檢為陰性本來無病，被篩檢為陽性本來無病，被篩檢

19、為陰性評價結果 Evaluation ResultsHave disease, test positiveHave disease, test negativeFree of disease, test positiveFree of disease, test negative評價結果 Evaluation Results 真實性（validity） 可靠性（reliability） 預測值（predictive value）二、篩檢試驗的評價指標Evaluation Index真實性（validity）也稱效度，指測量值與實際值相符合的程度，故又稱準確性(accuracy)Validity

20、 of test refers to the ability of test to provide a good indication of which apparently well individuals are truly diseased or not diseased.靈敏度（sensitivity）假陰性率（false negative rate）篩檢試驗(screening)金標準(gold standard)合計(total)患者(patient)非患者(non-patient)陽性(positive)真陽性(TP) A假陽性(FP) BR1陰性(negative)假陰性(FN

21、) C真陰性(TN) DR2合計(total)C1C2N真實性（validity）特異度（specificity）假陽性率（false positive rate）篩檢試驗(screening)金標準(gold standard)合計(total)患者(patient)非患者(non-patient)陽性(positive)真陽性(TP) A假陽性(FP) BR1陰性(negative)假陰性(FN) C真陰性(TN) DR2合計(total)C1C2N真實性（validity）正確指數(shù)（Youdens index） （特異度靈敏度）1 1（假陽性率假陰性率）真實性（validity）篩檢試驗

22、(screening)金標準(gold standard)合計(total)患者(patient)非患者(non-patient)陽性(positive)真陽性(TP) A假陽性(FP) BR1陰性(negative)假陰性(FN) C真陰性(TN) DR2合計(total)C1C2N陽性似然比(positive likelihood ratio，LR）陰性似然比(negative likelihood ratio，LR） 真實性（validity）篩檢試驗(screening)金標準(gold standard)合計(total)患者(patient)非患者(non-patient)陽性(p

23、ositive)真陽性(TP) A假陽性(FP) BR1陰性(negative)假陰性(FN) C真陰性(TN) DR2合計(total)C1C2N靈敏度（sensitivity） 特異度（specificity）假陽性率（false positive rate） 假陰性率（false negative rate）陽性似然比(positive likelihood ratio，+LR）陰性似然比(negative likelihood ratio, LR）正確指數(shù)（Youdens index）？真實性（validity）可靠性（reliability）也稱信度、精確度(precision)或可

24、重復性(repeatability) 指在相同條件下用某測量工具(如篩檢試驗)重復測量同一受試者時獲得相同結果的穩(wěn)定程度 Validity refers to the ability of test to give consistent results on repeat examinations of the same individual under the same conditions. 標準差與變異系數(shù) coefficient of variance，CV符合率（agreement rate）與Kappa值Screening test 2Screening test 1TotalPo

25、sitiveNegativePositiveABR1NegativeCDR2TotalC1C2N可靠性（reliability） 一致率（agreement rate），符合率一致率可靠性（reliability）Screening test 2Screening test 1TotalPositiveNegativePositiveABR1NegativeCDR2TotalC1C2N取值范圍：-1和1之間Range: between -1 and +1 Kappa值判斷標準Kappa值一致性強度0弱00.2輕0.210.40尚好0.410.60中度0.610.80高度0.811最強可靠性（r

26、eliability）Screening test 2Screening test 1TotalPositiveNegativePositiveABR1NegativeCDR2TotalC1C2NKappa值 = 實際一致性/非機遇一致性觀察一致性(Observation consistency) 機遇一致性(Opportunity consistency) 非機遇一致性(Non-opportunity consistency)實際一致性(Actual consistency)可靠性（reliability）Screening test 2Screening test 1TotalPositi

27、veNegativePositiveABR1NegativeCDR2TotalC1C2N 影響可靠性的因素 Determinants of reliability Biological variations of subjectsVariations in different observersVariations in different lab condition受試對象生物學變異觀察變異實驗室條件Screening testGold standardTotalPatientNon-patientPositiveTrue Positive AFalse Positive BR1Negati

28、ve False Negative CTrue Negative DR2TotalC1C2N預測值（predictive value）陽性預測值(positive predictive value PPV) 指篩檢試驗陽性結果中真正患病(真陽性)的比例Screening testGold standardTotalPatientNon-patientPositiveTrue Positive AFalse Positive BR1Negative False Negative CTrue Negative DR2TotalC1C2N預測值（predictive value）陰性預測值(nega

29、tive predictive value NPV)指篩檢試驗陰性者不患目標疾病的可能性 第二節(jié) 篩檢試驗的評價例 人群某病患病狀況與篩檢結果的關系 80 245 730 775 210 810 1020篩檢試驗 金標準 合計 患者非患者陽性ABR1陰性CDR2合計C1C2N靈敏度78.6特異度90.1假陽性率9.9假陰性率21.4正確指數(shù)0.69陰性似然比0.24陽性似然比7.94陰性預測值94.2陽性預測值67.3靈敏度、特異度、患病率與預測值的關系Relationship between sensitivity, specificity, prevalence and predict v

30、alueScreening tests use an arbitrary cut-off to separate two populations (normal vs. abnormal)NumberMeasurementTest with High SensitivityNormalAbnormalA negative result allows you to rule-out whatever you are testing - result+ resultSnNoutScreening tests use an arbitrary cut-off to separate two popu

31、lations (normal vs. abnormal)NumberMeasurementTest with High SpecificityNormalAbnormalA positive result allows you to rule-in whatever you are testing - result+ resultSpPinRelationship between predict value and SN, SPNumber of personsMeasurementNormal AbnormalacdbSN=a/(a+c) 100%, -PV=d(d+c) 100%,SP=

32、d/(b+d) 100%, +PV=a(a+b) 100%,2022/10/6篩檢Example: low prevalence 1% of people have disease out of 1,000 tested (PRE-TEST PROBABILITY) + - + 999 + PV - 1 891 - PV 10 9,990 Sensitivity Specificity 90% 90%2022/10/6篩檢How about a 50% pre-test prob50% of people have disease out of 1,000 tested + - + 450 5

33、0 - 50 450 sitivity Specificity 90% 90%2022/10/6篩檢Lets say its really high: 99%If 99% of people have disease out of 1,000 tested: + 891 1 New- 99 9 Sensitivity Specificity 90% 90%影響預測值的因素疾病的患病率患病率下降，陽性預測值降低靈敏度在患病率不變的情況下，隨著靈敏度的升高，陰性預測值升高，陽性預測值下降特異度隨著特異度的升高，陽性預測值升高，陰性預測值下降圖77 病人與非病人觀測值分布類型三、篩檢試驗截斷值的確定

34、Determination of screening cut-off point 非病人病人某項診斷標準的數(shù)值截斷點Threshold三、篩檢試驗截斷值的確定Determination of screening cut-off point 理想情況Ideal situation人數(shù)NumberNormalDisease非病人Normal病人Abnormal某項診斷標準的數(shù)值Cut-off三、篩檢試驗截斷值的確定Determination of screening cut-off point 實際情況Actual situation人數(shù)Population 96% sensitive 98% s

35、pecific100% sensitive 80% specific 50% sensitive100% specific非病人病人Sensitivity vs. Specificity sensitivity and specificity in different blood sugar level blood sugar SN SP blood sugar SN SP（mg/100ml） （） （） （mg/100ml） （） （ ） 80 100.0 1.2 150 64.3 96.1 90 98.6 7.3 160 55.7 98.6 100 97.1 25.3 170 52.9 9

36、9.6 110 92.9 48.4 180 50.0 99.8 120 88.6 68.2 190 44.3 99.8 130 81.4 82.4 200 37.1 100.0 140 74.3 91.2Relationship between sensitivity and specificity靈敏度與特異度的關系如果疾病的預后差，漏掉病人可能帶來嚴重后果，且目前又有可靠的治療方法，則臨界點可向左移，盡可能多的發(fā)現(xiàn)人群中的可疑病人，但會使假陽性增多如果疾病的預后不嚴重，而現(xiàn)有診療方法不甚理想，臨界點可右移，以降低靈敏度，提高特異度，盡可能將非患者鑒別出來，但增加了假陰性如果假陽性者作進一步

37、診斷的費用太貴，為了考慮節(jié)約經(jīng)費，可將篩檢試驗陽性結果的臨界點向右移如果靈敏度和特異度同等重要，可將篩檢試驗陽性結果的臨界點定在非病人的分布曲線與病人的分布曲線的交界處 篩檢試驗陽性結果的臨界點的確定Decision of screening cut-off point用真陽性率和假陽性率作圖得出的曲線，可用于確定篩檢試驗的截斷值。A receiver operating characteristic (ROC), or simply ROC curve, is a graphical is a graphical plot of the sensitivity, or true positi

38、ves, vs. (1 specificity), or false positives, for a binary classifier system as its discrimination threshold is varied. 受試者工作特性曲線 Receiver operator characteristic curve, ROC糖尿病血糖試驗不同血糖水平的靈敏度和特異度分布sensitivity and specificity in different blood sugar level 餐后2小時血糖mg/100ml）靈敏度（）特異度（）7098.68.88097.125.5

39、9094.347.610088.669.811085.784.112071.492.513064.396.914057.199.415050.099.616047.199.817042.9100.018038.6100.019034.3100.020027.1100.0血糖測定診斷糖尿病的ROC曲線截斷點Cutoff pointROC curve for diagnosis of diabetes using blood glucose橫軸表示假陽性率(1-特異度)縱軸表示真陽性率(靈敏度)點代表篩檢試驗的特定陽性標準值相對應的靈敏度和特異度對子 ROC曲線也可用來比較兩種和兩種以上診斷試驗的

40、診斷價值，從而幫助臨床醫(yī)師作出最佳選擇 CT和放射性核素腦掃描診斷腦瘤的ROC曲線In comparing two diagnostic tests, the test with the largest area under the ROC curve will have the fewest false positives and false negatives. 第三節(jié) 篩檢效果評價 Evaluation of effectiveness一、收益選擇患病率高的人群選用高靈敏度的篩檢試驗采用聯(lián)合試驗串聯(lián)(系列試驗）并聯(lián)（平行試驗）YieldTo select the population w

41、ith high prevalence rate To select the test with high sensitivity To design a combine test Series testParallel test 聯(lián)合試驗 (Combine test )在實施篩檢時，可采用多項篩檢試驗檢查同一受試對象，以提高篩檢的靈敏度或特異度，增加篩檢的收益，這種方式稱為聯(lián)合試驗。A combine test indicate that several tests would be used for a patient, thus, as a whole program, this met

42、hod could increase the tests sensitivity or specificity and enhance yield. 聯(lián)合試驗(Combine test )串聯(lián) 全部篩檢試驗結果均為陽性者才定為陽性可以提高特異度When all tests used turned out positive, the test program reach to a positive result. Series test can increase specificity than one single test, but decrease the sensitivity. 聯(lián)合試

43、驗(Combine test )并聯(lián) 全部篩檢試驗中，任何一項篩檢試驗結果陽性就可定為陽性。可以提高靈敏度When one of the tests used turned out positive, the test program reach to a positive result.Parallel test can increase sensitivity than one single test but decrease the specificity. 第三節(jié) 篩檢效果的評價OB和OA聯(lián)合試驗篩檢大腸癌結果The found colorectal cancer patients number of combined test 試驗結果 Test results 大腸癌病人Patients非大腸癌病人Not diseased OBOA+-193-+2316+272-669合計 7590第三節(jié) 篩檢效果的評價糞便隱血試驗（OB）靈敏度61.33特異度94.44糞便隱白蛋白試驗靈敏度66.67特異度80串聯(lián)試驗靈敏度36特異度97.78并聯(lián)試驗靈敏度92特異度76.67二、篩檢的生物學效果評價Biological effectiveness evaluation病死率、死亡率、生存率篩檢組Screened group未篩檢組Unscreened group比較Fata