Evidence-based Medicine A clinical skill that provides you with the tools you need to find important new medical research quickly and easily and to work out its implications for your clinical practice

Evidence-based Decision Making Clinical Expertise “Explicit, judicious, and conscientious use of current best evidence from medical care research to make decisions about the medical care of individuals” Clinical expertise IS important! Why? Experience with patients: improves efficiency of diagnosis and treatment Improves ability to determine applicability of research data to your patients Allows consideration of patient preferences EBM is the process of systematically finding the most recent applicable research, appraising its validity, and using it as the basis for clinical decisions. Clinical Expertise improves efficiency of Dx and Rx considers patient preferences Overestimates usefulness of therapy -placebo effect - loss to follow-up “Have not all concerned physicians been doing this (EBM) for ages... ? The steps and recommendations of the EBM acolytes reek of obfuscations and platitudes.” WKC Morgan, London, Ontario Lancet, October 28, 1995 Research Evidence Patient Preferences

執行EBM的五個步驟 ( I ) 1.問問題（可以回答的問題） 2.找資料（可獲得最好的證據資訊） 3.分析判斷（文獻的效度與重要性） Converting the need for information into an answerable question. 2.找資料（可獲得最好的證據資訊） Search the database and tracking down the best evidence. 3.分析判斷（文獻的效度與重要性） Critical appraising that evidence for its validity and importance.

執行EBM的五個步驟 ( II ) 4.臨床應用（整合三大層面） 5.評估成果（執行EBM的效率） Integrating the critical appraising with our clinical expertise and our patient’s unique biology, values and circumstances. 5.評估成果（執行EBM的效率） Evaluating our effectiveness and efficiency in executing step 1- 4 and seeking ways to improve them both for next time.

Question Forming

Why We Need to Form Questions ? Identify our knowledge gap Confirm the content of a question Guide the direction of literature search Train to generate questions Prioritize questions to be answered

Background questions Ask for general knowledge about a disorder Two components: A question root (who, what, where, when, how, why) What is the disorder ? What causes it ? How does it present ? What are some treatment options ? A disorder, or an aspect of disorder Background resources: textbooks, narrative reviews in journals (Online Harrison, UpToDate) Answering only background questions is insufficient to help getting the best available care to our patients

Foreground questions Ask for specific knowledge about managing patients with a disorder Four (or three): PICO Patient and/or problem Intervention (exposure, test) Comparison intervention (if relevant) Outcomes PECOT

Formulate A PICO Question Patient or population Describes patient (age, sex, race, past medical history, etc) A 50 year-old woman with a family history of breast cancer I Intervention What happens or is to be done; treatment, diagnostic test, exposure, screening Hormone replacement therapy C Comparison Compared to what? Nothing, placebo, gold standard, another intervention Placebo O Outcomes What is the effect of the intervention? (Be specific, mortality after a particular time period, hospitalizations) Prevention of Alzheimer’s disease

Determining question type Therapy Determining the effect of different treatments on improving patient function or avoiding adverse events Harm Ascertaining the effects of potentially harmful agents ( including the vary therapies we would be interested) on patient function, morbidity, and mortality Diagnosis (tests) Establishing the power of an intervention to differentiate between those with & without a target condition of disease Prognosis Estimating the future course of a patient’s disease Economic analysis, quality of life measurement …….

Formulate an Answerable Question Patient or Population: __________________ Intervention or Indicator: ________________ Comparator: _________________________ Outcome: ___________________________ Question sentence: _____________________ _____________________________________ Think about: What type of question is this ? What would be the ideal study type ? What would be the best feasible study type ?

Keywords from PICO Item Scenario - You are interested in whether statin is effective in reducing CV risk and mortality rate in DM patients Question Population – in DM patients does Intervention –statin therapy Comparator – placebo Outcome – reduce CV event risk and mortality rate? Time- in?years HIDE Underline the key terms Number the order of importance from 1-4

Keywords from PICO Item Scenario - You are interested in whether statin is effective in reducing CV risk in DM patients Question Population – in DM patients does Intervention – statin therapy Comparator – placebo Outcome – reduce CV event risk? 3 1 HIDE 2

Design Search Strategy Primary Term Synonym 1 Synonym 2 P ( OR OR ) AND I ( OR OR ) AND C ( OR OR ) AND O ( OR OR ) AND Cochrane Search Hits PubMed Search

MeSH Terms Medical Subject Headings Adrenergic beta antagonist Beta blockers

The "5S" levels of organisation of evidence from healthcare research Brian Haynes, R Evid Based Med 2006;11:162-164 UpToDate DynaMed ACP PIER BMJ Clinical Evidence ACP journal club Evidencebasedmedicine.com Cochrane Library BMJ Evidence Updates Other Systematic reviews eg. PubMed systematic reivew PubMed SUMsearch TRIP Google Copyright ©2006 BMJ Publishing Group Ltd.

Study Validity RAAMbo AA PICO p E C Represent Allocation or Adjusted Accounted for Outcome + a b Measure blind or objective T Outcome - c d

AA PICO Answer Author Patient Intervention Comparison Outcome Time 文獻試圖回答什麼問題？ 是否回答我的問題？ Author 作者是誰，是否為這方面的專家 有無利益衝突 Patient 是否隨機取樣(randomization) 取樣是否具代表性(representative) Intervention 是否有清楚的描述(Ascertain) 是否實際可行 Comparison Outcome 是否有客觀雙盲的測量(MBO) 是否有統計學或臨床上的意義？ Time 是否清楚描述研究取樣、操作、結果測量的時間點，追蹤時間是否夠長

Critical Appraisal of Therapy Study “治療研究”的評析 Are the results of the trial valid (效度如何)？ Was the assignment of patients to treatment randomised (是隨機分配嗎)？ Were the groups similar at the start of the trial (試驗開始時兩組條件是否相似)？ Aside from the allocated treatment, were groups treated equally (兩組其他治療條件一樣)？ Were all patients who entered the trial accounted for and were they analysed in the groups to which they were randomised (所有進入試驗者皆列入統計，並依所分配的組別計算)？ Were measures objective or were the patients and clinicians were blinded (結果的測量客觀，受試者及醫師都不知道所接受的治療為何)？ What were the results (結果為何)？ How large was the treatment effect (治療效果有多大)？ How precise was the estimate of the treatment effect (治療效果的預測多準確)？ Will the results help me in my patient care (適用於我的病人嗎)？

Was the assignment of patients to treatment randomised 是隨機分配嗎？ 最理想狀況為何？ 何處找到相關訊息？ 理想狀況是以中央電腦隨機分配，尤其是跨中心的研究 較小型臨床試驗也可以“獨立人士”執行隨機分配　　　　 “研究方法”應敘述受試者如何做分配，是否隱藏式隨機分配 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

Were the groups similar at the start of the trial 試驗開始時兩組條件是否相似？ 最理想狀況為何？ 何處找到相關訊息？ 如果隨機分配的方式及過程無誤，實驗組與對照組應該相似 應有統計比較兩組是否有差異　　　 “研究結果”的table I比較兩組之間可能影響研究結果的基本條件及變異因子的差別，如年齡、性別、致病危險因子等 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

Aside from the allocated treatment, were groups treated equally 兩組其他治療條件一樣？ 最理想狀況為何？ 何處找到相關訊息？ 除了要研究的治療方式或檢驗外，兩組病人所接受的其他治療都一樣 “研究方法”中所敘述的追蹤計劃，允許的追加治療 “研究結果”中兩組實際接受各項額外治療的種類與比例 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

最理想狀況為何？ 何處找到相關訊息？ □是 □否 □不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿ Were all patients who entered the trial accounted for and were they analysed in the groups to which they were randomised 所有進入試驗者皆列入統計，並依所分配的組別計算？ 最理想狀況為何？ 何處找到相關訊息？ 追蹤過程中病人流失越少越好，流失率應低於20% 達到研究結果的病人數太少時，即使流失率低，研究結論仍可能有偏差 統計分析時應按照病人隨機分配的組別計算(Intention-to-treat analysis) “研究結果”中應說明多少病人接受隨機分配 (table I)，多少病人進入統計分析。病人流失的數目、原因 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

最理想狀況為何？ 何處找到相關訊息？ □是 □否 □不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿ Were measures objective or were the patients and clinicians were blinded 結果的測量客觀，受試者及醫師都不知道所接受的治療為何？ 最理想狀況為何？ 何處找到相關訊息？ 雙盲試驗：研究者與受試者皆不知道受試者所接受的治療為何 結果評估的客觀性：結果的判斷若是客觀的（如死亡）較無爭議，但若結果的判斷是主觀的（如症狀、功能、能力）則評估者就不能知道病人是對照組或治療組 “研究方法”應說明對照組如何做偽裝治療，如給予外觀一樣的安慰劑 “研究方法”應說明如何做結果評估，評估者是否知道病人接受的治療為何 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

How large was the treatment effect 治療效果有多大？ 某一研究追蹤二年，對照組死亡率15%，治療組死亡率10%， 結果的呈現方式有： 呈現方式 代表的意義 Relative Risk (相對風險) RR = 0.10 / 0.15 = 0.67 治療組發生風險相對於對照組的倍數。RR=1兩組無差別，RR<1治療可降低風險， RR>1治療會增加風險 RR<1表示治療可降低死亡的風險 Absolute Risk Reduction (絕對危險性降低度) ARR = 0.15 – 0.10 = 0.05 or 5% 治療組與對照組發生風險的絕對差異 治療的益處是降低5%的死亡率 Relative Risk Reduction (相對風險性降低度) RRR = 0.05 / 0.15 = 0.33 or 33% Or RRR = 1 – 0.67 = 0.33 or 33% 相對於對照組，治療組降低風險的比率 (最常見的呈現方式) 相對於對照組，治療可以降低死亡的的機率33% Number Needed to Treat (益一需治數) NNT = 1 / ARR = 1 / 0.05 = 20 要預防一位不良結果發生所必需治療的病人數 必需治療20位病人2年才能預防1人死亡

How precise was the estimate of the treatment effect 治療效果的預測多準確？ The true risk of the outcome in the population is not known The best we can do is to estimate the true risk based on the sample of patients in the trial We can gauge how close this estimate is to the true value by looking at the confidence intervals (CI) Narrow CI represents a precise reflection of the population value The CI also provides us with information about the statistical significance of the result If the value corresponding to no effect falls outside the 95% CI then the result is statistically significant at the 0.05 level If the CI includes the value corresponding to no effect then the results are not statistically significant

Will the Results Help Me in Caring for My Patients ? Are the people in the study like my patient ? Age General state of health Type and severity of disease process Time in the course of the disease Did the study cover all aspects of problem ? eg treatment effect on symptom relief, quality of life, mortality etc Is the treatment feasible in my setting ? Will the potential benefits of treatment outweigh the potential harms of treatment for my patients ? Does it suggest a clear and useful plan of action ? Help to clarify a patient’s prognosis Suggest a useful plan to improve patient’s state of health

Critical Appraisal of Diagnostic Accuracy Study “診斷工具”的評析 Are the results of the study valid (效度如何)？ Was the diagnostic test evaluated in a representative spectrum of patients (是否經過具有代表性的病人群測試過)？ Was the reference standard ascertained regardless of the index test result (標準診斷工具做確診時不知道指標診斷工具的結果)？ Was there an independent, blind comparison between the index test and an appropriate gold standard of diagnosis (標準診斷工具與指標診斷工具是在獨立且雙盲的情況下進行比較)？ What were the results (結果是甚麼)？ Are test characteristics presented (呈現指標診斷工具的特性)？ Can we apply to our patient (可以應用到我的病人嗎)？

最理想狀況為何？ 何處找到相關訊息？ 指標診斷工具最好經過疾病各層面病人的測試，如不同嚴重程度、不同時期 Was the diagnostic test evaluated in a representative spectrum of patients 是否經過具有代表性的病人群測試過？ 最理想狀況為何？ 何處找到相關訊息？ 指標診斷工具最好經過疾病各層面病人的測試，如不同嚴重程度、不同時期 最好病人亦能隨機選擇或連續選擇以減少偏差 “研究方法”應說明如何選入病人，是否隨機選擇，病人的來源，是否具有代表性 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

最理想狀況為何？ 何處找到相關訊息？ □是 □否 □不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿ Was the reference standard ascertained regardless of the index test result 標準診斷工具做確診時不知道指標診斷工具的結果？ 最理想狀況為何？ 何處找到相關訊息？ 理想的情況是所有病人都應接受標準診斷工具及指標診斷工具的檢驗 若標準診斷工具是侵入性或昂貴檢查時，則可以選擇指標診斷工具檢查結果陰性者為之 或經一段適當時間的追蹤以確定是陰性結果 “研究方法”應說明標準診斷工具是否用於測試所有病人，或是用其他取代方法 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

最理想狀況為何？ 何處找到相關訊息？ □是 □否 □不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿ Was there an independent, blind comparison between the index test and an appropriate gold standard of diagnosis 標準診斷工具與指標診斷工具是在獨立且雙盲的情況下進行比較？ 最理想狀況為何？ 何處找到相關訊息？ 標準診斷工具的選擇是否恰當，有時候單一診斷工具無法做確定診斷，必需結合其他工具以確定疾病的存在 標準診斷工具與指標診斷工具是獨立分開執行且是雙盲的 檢查結果的判讀者並不知道另一項檢查的結果為何 “研究方法”應敘述所選用的標準診斷工具為何，必要時應做背景資料的搜尋，看所選擇的工具是否恰當 “研究方法”中亦應闡明兩種檢查由誰執行，如何進行，是否獨立雙盲 □是　　　　　　　□否　　　　　　　□不清楚 評論：＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿＿

Are test characteristics presented 呈現指標診斷工具的特性？ 診斷工具的研究，結果常以兩種方式呈現： 檢驗或檢查的準確度 Sensitivity (敏感度) Sn Specificity (特異度) Sp 檢驗或檢查在某一群體的預測值 Positive predictive value (陽性預測值 ) PPV Negative predictive value (陰性預測值 ) NPV

Test Characteristics LR+ = Sensitivity / (1-specificity) 0.96 / (1 – 0.8) = 4.8 LR- = (1-sensitivity) / specificity (1 – 0.96) / 0.8 = 0.05 Pre-test odds = prevalence / (1 - prevalence) 0.25 / 0.75 = 0.3333 Post-test odds = pre-test odds X likelihood ratio 0.3333 X 4.8 = 1.5998 Post-test probability = post-test odds/(post-test odds + 1) 1.5998 / (1.5998 + 1) = 0.6154

The Likelihood Nomogram

Can we apply the results to our patient ？ (可以應用到我的病人嗎) Patients Are your patients similar enough that the prevalence of the disease in the study population is similar to that in your patients ? Is the severity of the disease in the test population similar to patients you are likely to see? Benefits Are there risks associated with the tests? Are these outweighed by the danger of an undiagnosed disease ?