Kuang-Hui Yu, M.D. Center for EBM, Chang-Gung Memorial Hospital

EBM 林 Kuang-Hui Yu, M.D. Center for EBM, Chang-Gung Memorial Hospital

Medical Education in the New Century Bioinformatics Patient-centered care Problem-based learning Evidence-based medicine

Evidence-Based Medicine Use of current best evidence in making decisions about the care of individual patients. EBM is the integration of best research evidence with clinical expertise and patient values. Dr Pt Ev

(EBM, Evidence-based Medicine) 流行料讀臨

Decision Making in Health Care Searching bibliographic databases Browse journals Ask colleagues Remember what you learned during your professional training Do no harm Textbooks EBM: Not only a skill but also an attitude change

Dr. Sydney Burwell, Dean of Harvard Medical School Half of what you are taught as medical students will in ten years have been shown to be wrong. And the trouble is, none of your teachers knows which half. Bias

Interpretation of evidence is subjective: it dependents on how you view it.

年臨流行念療行都療立年立 (Iain Chalmers, David Sackett) Lancet Cochrane Collaboration 臨類

Conscientious, explicit, and judicious use of current best evidence in making decisions about individual patients. ~ Archie Cochrane 1972 Systemic review Meta-analysis analysis

McMaster University HIRU Health Information Research Unit Cochrane Collaboration http://hiru.mcmaster.ca/ Oxford University Centre for Evidence- Based Medicine http://cemb.jr2.ox.ac.uk American College of Physician ACP ACP Journal Club Online http://www.acpjc.org

The Evidence Pyramid Randomized Controlled Studies Cohort studies Case Control Studies Case series / Case reports Ideas, Editorials, Opinions Animal research In vitro (test tube) research Randomized Controlled Double Blind Studies 度 (Bias) Meta-analysis analysis Forest plot Meta - analysis

The purpose of meta-analysis analysis Employ statistical techniques in concert with a systemic qualitative review Increase statistical power for average estimate Resolve issues relating to conflicting results from studies Generate new hypothesis Glass, 1976 the statistical analysis of a large collection of analysis results from individual studies for the purpose of integrating the findings

What Does EBM Achieve Refinement and reduction Efficiency 率 Generalizability and consistency 類 Reliability and precision 度 Systemic review meta-analysis

行行 1. Formulate an answerable question. 臨料臨 2. Track down the best evidence. 料料 3. Critically appraise the evidence for validity, impact, and applicability. 度臨 4. Integrate with our clinical expertise and patient values. 療臨 5. Evaluate our effectiveness and efficacy.

Why EBM 臨不不率來率來不了度臨療易療利

料 1. 料路立見路更 update 料不便了論不利省讀量臨流行

參

行 Five Steps to Practice EBM Step 1. Converting the need for information (about prevention, diagnosis, prognosis, therapy, causation, etc.) into an answerable question. Step 2. Searching the best evidence with which to answer that question. Step 3. Critically appraising the evidence for its validity (closeness to the truth), impact (size of the effect), and applicability (usefulness in our clinical practice). Step 4. Integrating the evidence with our clinical expertise and patients unique biology, values and circumstances. Step 5. Evaluating our effectiveness and efficiency in executing steps 1-4 and seeking ways to improve them both for next time.

Asking Answerable Clinical Questions Well-built Clinical Question Background question Ask general knowledge about a disorder Have two essential components: A question root (who, what, why, when ) with a verb A disorder, or an aspect of a disorder Foreground question Ask for specific knowledge about managing patients with a disorder Have four (or three) essential components (PICO): 1. Patient and/or problem 2. Intervention (treatment) 3. Comparison intervention 4. Outcomes

There are four elements of a well-formulated question (PICO)( Patient ~ Who is the patient or what is the problem being addressed? Intervention ~ What is the intervention? Comparison ~ What are the alternatives? Outcome ~ What are the outcomes?

Types of Clinical Questions 臨類 What are the features / causes? What is frequency of the problem? Who has the problem? (Diagnosis( Diagnosis) Who will get the problem? (Prediction( Prediction) How can we alleviate the problem? (Intervention, Therapy)

Asking Answerable Clinical Question Patient/Problem Intervention Comparison Outcomes Insulin-dependent diabetics Intensive insulin regimen Regular insulin regimen Retinopathy Symptomatic hypoglycemia Do anticoagulants improve outcomes in patients with acute ischemic stroke versus no treatment?

Searching The Best Evidence 料論料料量讀

料 1. ACP Journal Club: 兩濾論理 2. DARE: Database of Abstracts of Reviews of Effectiveness 錄論料論 3. CDSR Cochrane Database of Systematic Reviews 路論療論 4. CCTR Cochrane Central Register of Controlled Trials 參料索來

EBM 料料來料類 ACP Journal Club 濾 50 例 NEJM JAMA Lancet Circulation. DARE CDSR CCTR NHS CRD Cochrane Cochrane Medline CINAL Biosis ERIC PsycINFO Medline EMBASE 料

Source of Evidence Cochrane library EBM reviews, DARE Medline Best evidence Clinical evidence Guidelines Clearinghouse Up to date, MD consult (Evidence is never enough)

路連 CGMH 館料 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/ 1. ACP Journal Club: http://www.acpjc.org/ (1-4, 7 ) 2. Cochrane ~ DARE (Database of Abstracts of Reviews of Effects) 3. CDSR (Cochrane Database of Systematic Reviews) ~ Collaborative Review Groups http://www.cochrane.org/cochrane/revabstr/crgindex.htm 4. CCTR (Cochrane Central Register of Controlled Trials): 5. Cochrane collaberation 6. NGC (National Guideline Clearinghouse): http://guideline.org 7. Micromedex (CCIS) 料更 8. Centre for Evidence-Based Medicine: http://www.cebm.net/ = http://cemb.jr2.ox.ac.uk 9. McMaster University HIRU Health Information Research Unit Cochrane Collaboration : http://hiru.mcmaster.ca/ 10. American College of Physician ACP : http://www.acponline.org 11. Bandolier: http://www.ebandolier.com = http://www.jr2.ox.ac.uk/bandolier/ 12. AHRQ website: http//www.ahrq.gov 13. InfoPOEMs: http://www.infopoems.com 14. Other resources: http://www.google.com.tw/ www.yahoo.com/ http://www.uptodate.com/ http://www.mdconsult.com/ 15. 16. 17. (HINT): http://www.hint.org.tw 連

The Evidence Pyramid Randomized Controlled Studies Cohort studies Case Control Studies Case series/ Reports Ideas, Editorials, Opinions Animal research In vitro (test tube) research Randomized Controlled Double Blind Studies Meta-analysis analysis Forest plot Meta - analysis Hierarchy of evidence that arranges study designs by their susceptibility to bias.

Grade of Recommendation [A] [B] Evidence-Based Medicine: How to Practice and Teach EBM. 2nd ed. David L. Sackett, Sharon E. Straus, W. Scott Richardson, William Rosenberg, R. Brian Haynes. Churchill Levingstone. 2000, p173-177 Level of Evidence 1a 1b 1c 2a 2b 2c 3a 3b Therapy Systemic review of RCTs Single RCT All-or-none Systemic review of cohort studies Cohort study or poor RCT Outcomes research Systemic review of casecontrol studies Case-control study [C] 4 Case series [D] 5 Expert opinion, physiology, bench research

The best evidence depends on the type of question What are the phenomena/problems? Observation What is frequency of the problem? (Frequency) Random (or consecutive) sample Does this person have the problem? (Diagnosis) Random (or consecutive) sample with gold standard Who will get the problem? (Prognosis) Follow-up of inception cohort How can we alleviate the problem? (Therapy) Randomized controlled trial (RCT) Best evidence is not always from RCTs.

臨

Critically Appraising the Evidence Critically appraising the evidence for its (VIP) Validity (closeness to the truth) 1. Was the assignment of patients to treatment randomized? 2. Was follow-up of patients sufficiently long and complete? (> 80%) 3. Were all patients analyzed in the groups to which they were randomized? (ITT) 4. Were patients and clinicians kept blind to treatment? 5. Were groups treated equally, apart from the experimental therapy? 6. Were the groups similar at the start of the trial? Validity: : selection bias, information bias, confounding Reliability of measurement: intraobserver (similarity over time), interobserver,, internal consistency SD, variance, CI (confidence interval) Impact (size of the effect): NNT (number needed to treat) = 1/ARR (absolute risk reduction) NNH (number needed to harm) = 1/ARI (absolute risk increase) Applicability plicability (usefulness in our clinical practice) Integrating the evidence with our clinical expertise and patients values and preferences.

讀論 Are the result valid? What are the results? (impact) Can I apply the results to the care of my patients? 林

臨類 (Risk) Cohort study Case-control study (Diagnosis) Sensitivity, specificity Predictive value (PPV, NPV) 療 (Therapy) Clinical trial, field trial (Prognosis) Prediction model, simulation model

數說數度異度率率療數度度罹療數

Determinants of Trial Quality Random allocation Allocation concealment Blinding~ single, double, triple blind Completeness of follow up 5-20 rule (at least 80% follow-up rate) Intension to treat (ITT) analysis vs. per protocol analysis

Calculation of OR/RR Treatment Exposed (experimental) Not exposed (control) Event Positive Negative A = 1 B = 29 C = 9 D = 21 EER = a/a+b = 0.033 (Cohort study, Clinical trial) CER = c/c+d = 0.30 Relative Risk = EER/CER = (a/a+b)/(c/c+d) = 0.11 Experimental event Odds = a/b = 0.034 (Case control study) Control event Odds = c/d = 0.43 Relative Odds = Odds Ratio = (a/b)/(c/d) = ad /bc = 0.08 Odd: a ratio of events to non-events ( )

Diagnostic test Diagnosis LR: likelihood ratio Disease (IDA) (ferritin) Present Absent Positive ( ) 731 a b 270 Negative ( ) 78 c d 1500 PPV NPV Sensitivity = a/a+c = 731/809 = 90% Specificity= d/b+d = 1500/1770 = 85% Positive predictive value (PPV) = a/a+b = 731/1001 = 73% Negative predictive value (NPV) = d/c+d = 1500/1578 = 95% LR+ for a positive result = sens/(1- spec) = 90%/15% = 6 (LR of a positive result = 度 /(1- 異度 ): 率 ) LR- for a negative result = (1-sens)/spec = 10%/85% = 0.12 Pre-test probability (prevalence)= = a+c/a+b+c+d= 31% Pre-test odds = prevalence/(1-prevalence) = 31%/69% = 0.45 Post-test test odds = Pre-test odds Likelihood Ratio Post-test probability= Post-test odds/(post-test odds + 1) (Multilevel Likelihood Ratio: not just provide a positive or a negative test result) SnNout, SpPin

Diagnosis Specificity (PPV) ( ) SnNout, SpPin Sensitivity (NPV) ( ) (predictive value) 行率 (prevalence) Positive predictive value (PPV) = Sen. P / [Sen. P + (1-Sp). (1-P)] (Bayes s theorem, P: probability, prevalence) P= 0.5, PPV= 0.8x0.5 / [0.8x0.5+0.2x0.5] = 0.8 = 80% P= 0.05, PPV= 0.8x0.05 / [0.8x0.05+0.2x0.05] = 17.4% 不 P 不 Specificity 行率 Sensitivity 行率參不行率來 Post-test test odds = Pre-test odds Likelihood Ratio (Pre-test odds) = 率 /(1- 率 ) (LR of a positive test result, LR+) = 度 /(1- 異度 ) ( 率 )

Diagnosis Use of Sensitivity Test ( 度 ) 來 Treatable disease Rule out disease ~ (SnNout) Use of Specificity Test ( 度 ) Rule in disease ~ (SpPin) ROC (receiver operator characteristic) curve 度 1- 異度率 ROC curve 度

Critically Appraising the Evidence 度 (Validity) (random allocation) (concealment of allocation) (follow-up duration) (> 80%) 療 blinded 利 intention-to-treat analysis 了療療兩療 baseline 讀什不了來臨來療來更

From RRR to ARR and NNT RRR ARR NNT

Asking Answerable Clinical Question Patient/Problem Intervention Comparison Outcomes Insulin-dependent diabetics Intensive insulin regimen Regular insulin regimen Retinopathy Symptomatic hypoglycemia

Treatment Effects Occurrence of diabetic retinopathy at 5 years among insulindependent diabetic in the DCCT trial Usual insulin regimen (CER: control event rate): 38% Intensive insulin regimen (EER: experimental event rate): 13% Risk Reduction (calculation): NNT Absolute risk reduction (ARR) = CER-EER = 38%-13% = 25% Relative risk reduction (RRR) = CER-EER /CER = 25%/38% =66% Number needed to treat (NNT) = 1/ARR = 1/25% = 4 patients NNT: The number of patients that need to be treated to prevent one bad outcome or get one good outcome.

Harm The proportion of patients with at least one episode of symptomatic hypoglycemia Usual insulin regimen (CER: control event rate): 23% Intensive insulin regimen (EER: experimental event rate): 57% Risk Increase (calculation): NNH Absolute risk increase (ARI) = EER - CER = 57% - 23% = 34% Relative risk increase (RRI) = EER-CER/CER = 57% - 23%/23% = 148% Number needed to harm (NNH) = 1/ARI = 1/0.34 = 3 patients ( 數 ) NNH: The number of patients that need to be treated to cause one bad outcome (being harmed). (Risk-adjustment for individual patients.)

Formulae to convert OR and RR to NNT For RR < 1: (Report of Systematic Reviews) NNT = 1/(1-RR) x PEER For RR > 1: NNT = 1/(RR-1) x PEER For OR < 1: NNT = 1 - [PEER x (1-OR)] / (1-PEER) x (PEER) x (1-OR) For OR > 1: NNT = 1 + [PEER x (OR-1)] / (1-PEER) x (PEER) x (OR-1) Absolute risk reduction (ARR) = CER-EER Relative risk reduction (RRR) = CER-EER/CER =ARR/CER, ARR = CER x RRR NNT = 1 / ARR = 1 / EER-CER = 1 / CER(=PEER) x RRR (Relative Risk = EER/CER, OR=EEO/CEO)

Calculation: NNT (95% CI)

行 Five Steps to Practice EBM Step 1. Converting the need for information (about prevention, diagnosis, prognosis, therapy, causation, etc.) into an answerable question. Step 2. Searching the best evidence with which to answer that question. Step 3. Critically appraising the evidence for its validity (closeness to the truth), impact (size of the effect), and applicability (usefulness in our clinical practice). (NNT, NNH) Step 4. Integrating the evidence with our clinical expertise and patients unique biology, values and circumstances. (LHH) Step 5. Evaluating our effectiveness and efficiency in executing steps 1-4 and seeking ways to improve them both for next time.

LHH (likelihood of being helped versus harmed) f t, f h : risk adjustment (Dr.) s: risk adjustment (Patient) Disease progression is 19 (0.95/0.05) (s: patient s s value)

Treatment of Class III-IV Lupus Nephritis Meta-Analysis Treatment of diffuse proliferative lupus nephritis: A meta-analysis of randomized controlled trials Am J Kidney Dis. 2004 Feb;43(2):197-208. Cochrane Renal Group Cochrane Database of Systematic Reviews. 1, 2004.

Forest plot This is a forest plot, with a vertical line at 1.0 representing equivalence in risk for an outcome with experimental and control treatment (null hypothesis). Values of RR less than 1 indicate a reduction in risk for the outcome with the experimental treatment. Conversely, values of RR more than 1 indicate an increase in risk. The RR for each outcome and its 95% CI are indicated by a solid square and a line. The 95% CIs are a measure of variability in the precision of the RR estimate and its statistical significance. The size of the solid square represents the contribution (weight) of the trial to the analysis. Diamond-shaped symbols represent the summary estimator of overall effect pooling the weighted effect of individual RCTs. Heterogeneity of treatment effects between studies was investigated by visual examination of graphic meta-analysis plots and from the Cochran Q (heterogeneity chi-square) and I 2 statistic.

Treatment of diffuse proliferative lupus nephritis: A meta-analysis of randomized controlled trials Am J Kidney Dis. 2004 Feb;43(2):197-208. Cochrane Renal Group Cochrane Database of Systematic Reviews. 1, 2004.

Principles of Doing a Systemic Review The same underlying effect Include all relevant studies Published or unpublished studies Dealing with heterogeneity (Cochrane Q) Problem of combining heterogenous studies Weighted average of effect 95% CI, weighting=1/variance High quality of primary studies Garbage in, garbage out Reproducible reliable procedures

Two Fundamental Principles of EBM EBM posits a hierarchy of evidence to guide clinical decision making. Evidence alone is never sufficient to make a clinical decision. Trade the benefits and risks Inconvenience Costs Consider the patient s value (Risk-adjustment for individual patient.)

Clinical Practice Guidelines 療療理利流量識療 (health care-provider) 識臨識行行不臨療 (clinical practice guideline) 療不療 EBM: Closing the Research-Practice Gap

Clinical Practice Guidelines Systemically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. Purpose ~ to make explicit recommendations with a definite intent to influence what clinicians do. 療

Choosing a Good Question Burden of disease or condition Intervention Ability to change practice Feasibility of assessment Others ~ ethical, political, and social consideration

Resource Centers for Guidelines NGC - National Guideline Clearinghouse http://www.guideline.gov AGREE - appraisal of guideline research & evaluation http://www.agreecollaboration.org/ Guidelines International Network http://www.g-i-n.net/ SIGN - Scottish Intercollegiate Guidelines Network http://www.sign.ac.uk/

Resource Centers for Guidelines Center for Evidence-based Medicine, Oxford http://www.cebm.net/ Cochrane collaboration http://www.cochrane.org/ Bandolier Links http://www.jr2.ox.ac.uk/bandolier/bandlink. html/ 臨療

Barriers to the practice of EBM Limited high-level evidence Limited systemic summaries of evidence Lack of facilities Easy access to evidence, computer reminders, CATs Lack of training Personal barrier, staff barrier, institutional barrier Anxiety about teacher s attitude toward EBM Attitude and behavior change Adult learning theory (postgraduate, undergraduate) Behavior change does not occurs unless physicians are convinced of the benefits of practicing EBM. Acad Med 2003;78:1183-90, Med Teach 2003;25:77-81

林良李料益 16 麗理論識念 Power Point 識便路料

林年練練例論臨論參 94.01~94.05 行六年 94.01.22 行來練

練臨療臨臨療立料不力量

EBM ~ Just do it. Knowledge is the enemy of disease Action is the enemy of knowledge Muir Gray ~ Oxford University Institute of Health Sciences, UK