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Study Designs and Applied Statistics Methods in the Clinical Research 振興醫院教學研究部 董道興 副研究員

Cheng-Hsin General Hospital. Study Designs and Applied Statistics Methods in the Clinical Research 振興醫院教學研究部 董道興 副研究員 2008.2.26. Cheng-Hsin General Hospital. Part I: Basic Study Designs. 研究設計的重要性. Cheng-Hsin General Hospital. 好的研究設計較能得到可信的研究結果 好的研究設計較能提供正確的因果關係.

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Study Designs and Applied Statistics Methods in the Clinical Research 振興醫院教學研究部 董道興 副研究員

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  1. Cheng-Hsin General Hospital Study Designs and Applied Statistics Methods in the Clinical Research 振興醫院教學研究部 董道興 副研究員 2008.2.26

  2. Cheng-Hsin General Hospital Part I: Basic Study Designs

  3. 研究設計的重要性 Cheng-Hsin General Hospital • 好的研究設計較能得到可信的研究結果 • 好的研究設計較能提供正確的因果關係

  4. Cheng-Hsin General Hospital 研究設計之分類 • 觀察性研究 • 1.個案研究與描述性研究(Case-series or Descriptive) • 2.橫斷研究(Cross-sectional studies) • 3.世代研究(Cohort or Prospective studies) • 4.病例對照研究(Case-control or Retrospective studies) • 5.歷史性世代研究 (Historical cohort studies)

  5. Cheng-Hsin General Hospital • 實驗性研究(Experimental studies) • 1. 控制性試驗(Controlled trials) • A. Parallel or concurrent controls • a. Randomized • b. Not randomized • B. Sequential controls • a. Self-controlled • b. Crossover • C. External controls (including historical) • 2.無控制組 • 統合性研究(Meta-analysis)

  6. 觀察性研究 Cheng-Hsin General Hospital • 個案研究 1. 針對某些特定病徵的病人進行描述 2. 無對照組(control group) 3. 無研究假設 (research hypotheses)

  7. Cheng-Hsin General Hospital

  8. Cheng-Hsin General Hospital 有病 • 橫斷研究(Cross-sectional studies) 研究樣本 沒病 Time 研究時間 No direction of inquiry Question: What is happening?

  9. 橫斷研究之特點 Cheng-Hsin General Hospital • 目的 1.描述健康狀態 2.分析因子與事件之相關 • 研究設計 同時間收集因子與疾病等變項 • 資料收集方法 1.病歷紀錄 2.觀察 3.面訪及電訪 4. 問卷填寫 • 優點 1. 簡單易行 2. 資料收集範圍廣闊 3. 較具經濟性 4. 可短時間內得到結果 5. 較易獲得大量樣本 • 缺點 1.無法判定因果關係(causal relationship) 2.推論易流於表面

  10. 1991-1993 A community-based screening regime for type 2 diabetes (n=12,489) Screening for type 2 diabetes (1991-1993) WHO (1999) criteria 1994-1998 Migrated out or death (n=152) Type 2 diabetics (n=1123) DR screening for Type 2 diabetics in 1999-2002 (n=971) Screening for diabetic retinopathy (1999-2002) Loss to follow-up (n=246) • Epidemiologic information • 1.Prevalence of DR • 2.Incidence of DR • .Risk factors of DR • .Natural history of DR 725 Type 2 diabetics received DR screening Economic evaluation of diabetic retinopathy screening (2003) Sight year measurement Utility survey Willingness-to-pay survey Economic evaluation 1. Cost-effectiveness analysis 2. Cost-utility analysis 3 .Cost-benefit analysis Cheng-Hsin General Hospital The Study Procedure

  11. Cheng-Hsin General Hospital

  12. Cheng-Hsin General Hospital 有病 暴露組 (exposed) • 世代研究(Cohort study) 研究世代 沒病 Direction of inquiry 有病 Question: What will happen? 非暴露組 (unexposed) 沒病 Time 研究起始點

  13. 世代研究之特點 Cheng-Hsin General Hospital • 目的 探討暴露組和非暴露組之間發生率(incidence)是否相同 • 研究設計 1.觀察世代可選擇一組或兩組 2.長期觀察研究世代之得病情形 • 優點 1.可計算發生率 2.可了解因果關係 3.可以調查稀有暴露世代的得病情形 4.可減少選樣性偏差的發生 5.可探討多重疾病(multiple diseases) • 缺點 1.觀察時間過長 2.費用較高 3.失去追蹤導致結果產生偏差(bias)

  14. Cheng-Hsin General Hospital 有病 沒病 • 主要測量指標 相對危險性(relative risk, RR) [a/(a+b)]/ [c/(c+d)] 相差危險性(attributable risk, AR) [a/(a+b)]-[c/(c+d)] 有暴露 沒暴露 a b a+b c d c+d a+c b+d a+b+c+d

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  17. Cheng-Hsin General Hospital • 成果評值(Outcome assessment) 1.功能狀態(Functional status) 2.生活品質(Quality of life) 3.滿意度(Patient satisfaction) 4.存活時間(survival time) 5.經濟評估(Economic evaluation) A.Cost-effectiveness analysis –CEA B.Cost-utility analysis –CUA C.Cost-benefit analysis –CBA

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  19. Cheng-Hsin General Hospital

  20. Cheng-Hsin General Hospital 暴露(exposed) • 病例對照研究(Case-control studies) 病例組(cases) 未暴露(unexposed) 暴露(exposed) 對照組(controls) 未暴露(unexposed) Time 研究起始時間 Direction of inquiry Question: What happened?

  21. 病例對照研究法之特徵 Cheng-Hsin General Hospital • 目的 探討病例組與對照組其暴露分布是否相同 • 研究設計 選擇一組有病者為病例組, 無病者為對照組, 比較病例組與 對照組間過去的暴露經驗 • 病例組與對照組之選擇 1.定義清楚所選擇的病例組個案 2.選擇具有代表性的對照組個案

  22. Cheng-Hsin General Hospital • 優點 1.迅速便宜 2.所須樣本數較小 3.適合於稀有疾病之研究 4.可快速得到結果 5.可以探討多重暴露對單一疾病的相關 • 缺點 1.不易得到過去完整的暴露經驗 2.不易選取合適的對照組 3.僅能用估計的方式得到發生率 4.時序性不易確定 5.可能產生選樣性偏差(selection bias)或 回憶性偏差(recall bias)

  23. Cheng-Hsin General Hospital 暴露 未暴露 病例組 a b a+b 對照組 c d c+d a+c b+d 1.藉著比較case及control組的exposed與unexposed的比值 (ratio),即比較a/b和c/d就可知exposure和disease是否有關 2.若case組暴露率較control組高 (a/b>c/d),表示暴露和發病 有正相關 3.case 組的exposure odds=a/b control 組的exposure odds=c/d 則odds ratio(OR)=(a/b)/(c/d)=ad/bc 如果OR值越高,表示暴露與發病越有正相關.

  24. Cheng-Hsin General Hospital

  25. Cheng-Hsin General Hospital 暴露組 (exposed) 有病 • 歷史性世代研究(Historical cohort studies) 研究世代 沒病 有病 Direction of inquiry 對照組 (unexposed) 沒病 Time 研究起始時間

  26. 觀察性研究設計之比較 Cheng-Hsin General Hospital 種類 過去 現在 未來 橫斷研究Subjects selected, data gathered on exposure status and outcome 病例對照研究Information Case chosen obtained on with outcome past exposure Controls chosen without outcome 世代研究Subjects selected outcome and classified as measured to exposure 歷史性世代研究Subjects identified Subjects who were exposed classified as to in the past exposure from existing records Outcome measured

  27. 實驗性研究(Experimental studies) Cheng-Hsin General Hospital • Experimental studies that involve humans are called clinical trials • Controlled trials are studies in which the experimental drug or procedure is compared with another drug or procedure, sometimes a placebo and sometimes the previously accept treatment • Uncontrolled trials are studies in which the investigators’ experience with the experimental drug or procedure is described, but the treatment is not compared with another treatment

  28. Cheng-Hsin General Hospital 有結果 實驗組 • 有對照組的實驗研究 研究樣本 無結果 對照組 有結果 無結果 Time 研究起始時間 介入(intervention)

  29. Cheng-Hsin General Hospital • 實驗組與對照組 1.接受實驗步驟的對象 所組成的團體稱為實驗組,未接受實 驗步驟者則稱為對照組 2.實驗組的介入因素包括:治療性、預防性、干預性、社區 性試驗對照組則使用安慰劑(placebo)

  30. Cheng-Hsin General Hospital • 隨機分派(Random Allocation) 1.研究對象簽了同意書之後,根據random allocation來分組, 通常採用隨機號碼表 2.Randomization=Random Allocation 指每一個研究對象被分到任一組的機率是一樣的 3.以隨機分派的方法來分配實驗組與對照組可以提高兩組 的可比較性(comparability),而避免自我選擇(self- selection)的誤差, 以建立資料分析結果的效度(validity) 4.隨機分派方式: (1)簡單隨機分派(simple randomization) (2)分區隨機分派(Block randomization) (3)分層隨機分派(Stratified randomization)

  31. Cheng-Hsin General Hospital • 盲目程序(Blinding procedure) 1.在評估實驗結果時,必須考慮研究者與參與者的bias,為了避免bias, 最好的方法就是double blind 2.單盲程序(single blind):實驗者知道,被實驗者不知道被分到哪一組 雙盲程序(double blind):實驗者和被實驗者都不知道會分到哪一組 三盲程序(triple blind):實驗者、被實驗者和資料分析者都不知道 3.雙盲或三盲程序有時不易做到: (1)副作用(side effect) (2)有些trial是home VS hospital (3)醫師必須知道patient是屬於哪一組,便於照顧病人的情況

  32. Cheng-Hsin General Hospital • Randomized clinical trials Provided the strongest evidence for concluding causation • Nonrandomized trials Do nothing to prevent bias in patient assignment • Trials with self-controls 1.Only one group in which patients are assessed before and after the intervention 2.Hawthorne effect

  33. Cheng-Hsin General Hospital with outcome experimental subjects experimental subjects with outcome • 交叉試驗(Crossover study) subjects meeting entry criteria without outcome without outcome with outcome with outcome controls without outcome controls without outcome Time washout period intervention onset of study intervention

  34. Cheng-Hsin General Hospital subjects with outcome • Trials with external controls without outcome with outcome Results from previous study without outcome Time onset of study intervention in subjects only

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  36. 類實驗研究 (Quasi-experimental study) Cheng-Hsin General Hospital

  37. 統合性研究(Meta-analysis) Cheng-Hsin General Hospital • Meta-analysis uses published information from other studies and combines the results so as to permit an overall conclusion • Meta-analysis is similar to review articles, but additionally includes a quantitative assessment and summary of the findings • Meta-analysis is especially appropriate when the studies that have been reported have small numbers of subjects or come to different conclusions

  38. 實驗設計評估 Cheng-Hsin General Hospital • How to evaluating the study design the medical literatures? 1.In a clinical trial (1) How are subjects recruited? (2) Are subjects randomly assigned to the study group? (3) Is there a control group? (4) Are appropriate therapies included? (5) Is the study blind? Double blind? (6) How is compliance evaluated? (7) If some cases are censored, is a survival method such as Kaplan-Meier or the Cox model used?

  39. Cheng-Hsin General Hospital 2. In a cohort study (1) How are subjects recruited? (2) Are subjects randomly selected from an eligible pool? (3) How rigorously are subjects followed? How many dropouts does the study have and who are they? (4) If some cases are censored, is a survival method such as Kaplan-Meier or the Cox model used? 3. In a case-control study (1) Are subjects randomly selected from an eligible pool? (2) Is the control group a good one? (3) Are records reviewed independently by more than one person?

  40. Cheng-Hsin General Hospital 4. In a cross-sectional study (1) Are the questions unbiased? (2) Are subjects randomly selected from an eligible? (3) What is the response rate? 5. In a meta-analysis (1) How is the literature search conducted? (2) Are the criteria for inclusion and exclusion of studies clearly stated? (3) Is an effort made to reduce publication bias? (4) Is there information on how many studies are need to change the conclusion?

  41. Cheng-Hsin General Hospital Part II: Basic Statistics Methods

  42. Types of clinical data analysis Cheng-Hsin General Hospital • Time-unrelated analysis • Time-related analysis

  43. Time-unrelated analysis Cheng-Hsin General Hospital • Categorical scale 1. Proportion Z test & 2 test 2. Logistic regression • Interval scale 1. Independent T-test (Two-sample) 2. ANOVA 3. Linear Regression

  44. Time-related analysis Cheng-Hsin General Hospital • Balanced repeated measurement 1.Categorical scale (1) Generalized Estimation Equation (GEE) (2) Mixed model 2.Interval scale (1) Pair T-test (2) Mixed model • Survival analysis

  45. Survival analysis Cheng-Hsin General Hospital • Non-parametric method Kaplan-Meier (Life-Table) method • Semi-parametric method  Cox regression model • Parametric method

  46. Two-Sample Problems Cheng-Hsin General Hospital • Continuous variable 1.Independent T-test 2.Paired T- test • Binary variable 1.Proportion Z Test or Chi-square test 2.McNemar’s Test

  47. Independent T-test & Paired T-test Cheng-Hsin General Hospital Example 1 : Evaluation of effectiveness of community rehabilitation care (n=30) Pre Post 83 77 95 80 75 70 62 59

  48. Statistical evaluation Cheng-Hsin General Hospital Mean Pre Post 78.20 70.26 (SD=14.31) (SD= 18.04) Paired T T=-3.09 P=0.0079 Independent T T=-1.33 P=0.19

  49. Correlation & Repeated measurement Cheng-Hsin General Hospital Paired T test enhance statistical efficiency by considering ...... the correlation between Pre- and Post- (the same individual)

  50. 2test & Proportion Z test Cheng-Hsin General Hospital Example 2 : • The study on the assessment of mental health program • Intervention: Experimental & Control • Outcome : Favorable (F) & Unfavorable (U)

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