3. "THE THREE MAIN TASKS OF THE CLINICIAN ARE DIAGNOSIS, PROGNOSIS, AND TREATMENT. OF THESE DIAGNOSIS IS BY FAR THE MOST IMPORTANT , FOR UPON IT THE SUCCESS OF THE OTHER TWO DEPENDS." RYLE J.A. The natural history of disease 2nd ed. Oxford University Press, 1948

4. What I will be sharing with you Today?

5. 1.What is evidence based laboratory medicine? 2.What are the components of EBLM? 3. How to ask a question? 4. How to acquire information? 5.How to analyze the information? 6.How to apply the information? 7.Critics view of EBLM.

6. What is Evidence based Medicine ?

8. EBLM Conscientious explicit and judicious use of current best evidence in Laboratory medicine for making well informed decision

9. Individual expertise Best external evidence Patients values & expectation EBLM COMPONENTS OF EBLM

10. Why evidence based Medicine?

11. Increased innovation New technologies Greater knowledge New treatments & Diagnostics Increased workload More patient visits More spending Salary and other costs Patient expectation More knowledge from internet Legal aspects

13. What are the justification for an evidence based medicine? Constant requirement for information Constant addition of new information Limited time availability The poor quality of access to good information

14. Limited number and poor quality of studies linking test Results to patients benefits. The poor perception of the value of diagnostic tests. The ever increasing demand for tests. The disconnected approach to resource allocation. Silo budgeting What is particular to laboratory medicine?

16. Elements of EBLM

18. PICO P I C O atient or Problem ntervention omparison utcome “ Patient” refers to the person presenting with the problem, or more simply, to the problem itself. Both concepts are important in searching.

19. PICO P I C O atient or Problem ntervention omparison utcome “ Intervention” refers to the action taken in response to the problem. This is often a drug or surgical procedure, but it can take many forms

20. PICO P I C O atient or Problem ntervention omparison utcome “ Comparison” refers to the benchmark against which the intervention is measured. Often it refers to another treatment, no treatment, or a placebo.

21. PICO P I C O atient or Problem ntervention omparison utcome “ Outcome” refers to the anticipated result of the intervention.

22. How to apply this for EBLM?

23. QUESTIONS TO BE ASKED CARO QUESTIONS C: Case What are the patient characteristics, conditions, symptoms, demographics ? A: Assay Which procedure or strategy is considered ? R: Reference What is the standard procedure, the comparator ? O: Outcome What is the interest, the diagnostic validity ? Sensitivity, specificity, predictive values, prognosis ?

24. Types of question

25. Type I : Regarding diagnostic accuracy of the test 1. Patients presenting to the emergency department With shortness of breath. 2. How well does N terminal pro B type natriuretic peptide 4. Predict heart failure as assessed by 3. The cardiac ejection fraction measured by Echocardiography

26. Type II : Related to the value of test in improving Patients outcomes. 1. Patient admitted to the hospital for treatment of heart failure. 2. How well does the use of N terminal Pro B type Natriuretic peptide as a guide to therapy. 3. Improve the length of hospital stay and the rate Of subsequent readmission for heart failure ?

27. How to Acquire evidence ?

28. In laboratory medicine an alternative to Clinical trail is Diagnostic accuracy studies. The best design for diagnostic accuracy Studies is a prospective cohort study with a Blinded comparison of the performance of Experimental test and that of an appropriate Gold standard test in a spectrum of patients Suspected to having the disease in question.

29. An important goal of studies of diagnostics test is to Determine whether the new test adds information to that known from patient observation or other investigations

30. How to start a search ?

31. Computer system Clinical Evidence or PIER (UpToDate) ACP Journal Club, InfoPOEMS, Dynamed Cochrane Library, PubMED Clinical Queries, BMJUpdates, guidelines Original Studies OR SUMsearch or TRIP How to seek evidence-based information

32. Choosing Resources Foreground Background Rare Common Unfiltered Database (e.g. MEDLINE) Filtered/ Pre-appraised Evidence Textbooks

33. Where to search ?

34. It is best to start the search with looking for External evidence based guidelines that can be Adapted. The search for evidence usually starts in databases Such as the Cochrane Library which contains high quality Systematic reviews or meta analysis.

35. If a search is not successful in the secondary Literature one can look for primary reports in the Medline. Use Pub Med for the search of Medline. The best single search term for laboratory test Is “ sensitivity “. However the word “diagnostic test”, “Diagnosis” “ Diagnostic use” combined with the corresponding Clinical condition ( eg: Chronic renal failure)and Finally the name of the test ( eg: Soluble transferrin Receptor.

36. Determine the level of evidence of the primary Studies and reviews. The highest level of evidence is a good quality well Conducted systematic review or meta analysis of RCT for testing patient related outcomes. ( PSA for Screening Prostate cancer ) Prospective cohort studies for Diagnostic accuracy studies. ( Total PSA Vs the free PSA / Total PSA in the diagnosis Of prostate cancer )

37. What and Why do we choose a systemic review?

38. Systematic Searching Systematic Reviews

40. Definitions Review articles A broad overview of a topic, similar to a textbook chapter. Studies are chosen using a standardized protocol to minimize selection bias. A type of review article that focuses on a focused clinical question Systematic Review

41. Definitions Review articles A broad overview of a topic, similar to a textbook chapter. Systematic Review A type of review article that focuses on a focused clinical question A type of systematic review in which the numerical results from individual studies are mathematically combined to give a single, overall estimate of treatment effect. Meta-analysis

46. How to critically appraise an Evidence?

48. HOW TO DETECT HETEROGENICITY?

49. Forrest Plots

50. D'Souza, A. L et al. BMJ 2002;324:1361 Effect of probiotics on the risk of antibiotic associated diarrhoea

51. Forest plots. These graphical displays show study data in a way that makes it easy to see similarities and differences between studies.

52. Look at the title of the forest plot, the intervention, outcome effect measure of the investigation and the scale

53. The label tells you what the comparison and outcome of interest are Effect of probiotics on the risk of antibiotic associated diarrhoea

54. Scale measuring treatment effect. Take care when reading labels! Effect of probiotics on the risk of antibiotic associated diarrhoea

55. The names on the left are the authors of the primary studies included in the MA

56. Each study has an ID (author) Effect of probiotics on the risk of antibiotic associated diarrhoea

57. Treatment effect sizes for each study (plus 95% CI) Effect of probiotics on the risk of antibiotic associated diarrhoea

58. The small squares represent the results of the individual trial results The size of each square represents the weight given to each study in the meta-analysis

59. Horizontal lines are confidence intervals Diamond shape is pooled effect Horizontal width of diamond is confidence interval Effect of probiotics on the risk of antibiotic associated diarrhoea

60. The vertical line represents the line of no effect, i.e. where there is no statistically significant difference between the treatment/intervention group and the control group

61. The vertical line in middle is the line of no effect For ratios this is 1, for means this is 0 Effect of probiotics on the risk of antibiotic associated diarrhoea

62. Pooled Se = 0.71 Heterogeneity p<0.001 Pooled Sp = 0.95 Heterogeneity p<0.001 Pai M, et al. Comparison of diagnostic accuracy of commercial and in-house nucleic acid amplification tests for tuberculous meningitis: a meta-analysis. Poster presented at the American Society for Microbiology, 2003

63. “ Average men having an average meal”

64. How to detect Bias?

68. Funnel Plot Sample size Favors Treatment Favors Control Odds Ratio

69. Funnel Plot Sample size Favors Treatment Favors Control Odds Ratio

70. Funnel Plot Sample size Favors Treatment Favors Control Odds Ratio

71. Funnel Plot Sample size Favors Treatment Favors Control Odds Ratio

74. Publication Bias Asymmetrical appearance of the funnel plot with a gap in a bottom corner of the graph

76. How to rate or grade the evidence?

77. Quality of primary studies and reviews Rating of the level of evidence of individual articles 1a 1b II III IV Meta analysis or systematic review based on at least several level 1b studies Diagnostic trial or outcome study of good quality Diagnostic trial or outcome study of medium quality Insufficient patients or other trials ( Case control or other designs) Descriptive studies , case reports etc Statement of committees, opinion of experts, not systematic

78. Rating of the strength of the evidence supporting Guidelines recommendations A B C D Supported by at least by two independent Studies of level 1b or one review of 1a Supported by at least two independent studies of level II Not supported by sufficient studies of level I of II Advices of experts

79. Compile an evidence table 1.Publication details of the individual studies. 2. Study design 3.Spectrum of patient and patient setting. 4.Prevalence of the condition. 5.Diagnostic test used of compared. 6.Out come measured. 7.Effects measured including measures of diagnostic accuracy.

80. 8. Comments on specific issues raised by the study. ( biases) 9.Quality rating and level of evidence of the study.

81. Make the judgment based on: 1.Quality of the evidence : The extent to which the study’s design, conduct, And analysis have minimized selection, measurement and Confounding bias. 2.Quantity of evidence: The number of studies that have evaluated the given Topic and the sample size of each study. 3. Consistency of the evidence.

84. Do we need a detailed statistical and epidemiological skills To practice EBLM ? No Then what is needed ? Critical appraisal skill Competent understanding of the strengths and weakness of systemic Reviews and meta analysis The laboratory personnel must direct more effect to demonstrate the impact of laboratory tests on a greater variety of clinical outcomes.

85. DIAGNOSIS WORKSHEET Are the Results of This Diagnostic Study Valid? Was there an independent, blind comparison with a reference (“gold”) standard of diagnosis? Was the diagnostic test evaluated in an appropriate spectrum of patients (like those in whom it would be used in practice)? Was the reference standard applied regardless of the diagnostic test result? Was the test (or cluster of tests) validated in a second, independent group of patients?

86. Can We Apply This Valid, Important Evidence About a Diagnostic Test in Caring for Our Patient? Is the diagnostic test available, affordable, accurate, and precise in our setting? Can we generate a clinically sensible estimate of our patient’s pre-test probability (from personal experience, prevalence statistics, practice databases, or primary studies)? Will the resulting post-test probabilities affect our management and help our patient? *Could it move acrosis a test-treatment threshold? *Would our patient be a willing partner in carrying it out? Would the consequences of the test help our patient?

87. STARD (Standards for reporting diagnostic accuracy) - a checklist P. M. Bossuyt et al. 2003 Introduction Diagnostic accuracy between tests or across patient groups Probands Demographic description, inclusion and exclusion criteria, symptoms, data collection criteria. Study design Time frame, number and group of probands, time of measurements, treatment of probands Reference standard Description of standard and rationale for comparison. Test method Technical, analytical specifications (linearity, cut-off levels, uncertainty, bias, etc) Statistical methods Methods for reporting diagnostic validities, comparisons between groups, test reproducibility Results Cross tabulaton of results (reference, test), analytical and diagnostic acuracy between groups of probands, ROC-curves, Box-Whiskers plot. Conclusion Clinical application

88. Decisions Cost effectiveness Organizational impact Clinical impact Diagnostic Therapeutic Outcome Diagnostic performance Technical performance Evidence of performance designed to facilitate decision making

89. How to act and Modify ?

90. Test Question Result Action Outcome Troponin I Has the patient had a MI 7.2µg/L Decide to admit, Intensive care Decreased morbidity & mortality BNP Is this breathless patient suffering from Heart failure 56ng/L Seek alternative diagnostic method Avoid incorrect diagnosis & treatment HbA1C Is this patient complying with treatment protocol 10.6% ( No change in a year Consider changing Treatment, closer monitoring and freq visit Persistently high value has increased risk of complications

91. Promises of EBLM It ties clinical practices to scientific standards of evidence Able to draw upon the objective experience of many researchers working with accepted scientific standards of evidence EBLM should also promote greater uniformity Evaluate implementing cost cutting measures EBM should provide a scientific basis for the construction of public policy

92. Critics Standard guidelines – Disincentives of individual innovation Becomes more like cook book medicine Lower standards by deskilling practitioners Instead to clinical judgment practitioners will be encouraged to Use protocols Incapable of operating effectively in diverse situation

93. Is the highest level of evidence always the strongest Recommendation ? NO

94. Highest level of evidence may not provide the Strongest recommendations in some local contest. The evidence must be supplemented with considered Judgment of the potential clinical benefits and harms Patients preferences The organizational and economic impact of testing.

95. In patients presenting with complaints with symptoms Of tongue and mouth the prevalence of Vit B12 Deficiency in only 8%. The relatively low cost of Testing for B12 deficiency And availability of effective treatment may counter Balance the low probability of this cause. Might lead to recommendation of B12 testing in One community . But not so in another community because the relative Costs may be different.

96. An example where patients choices are considered Is the triple test used for antenatal screening of Downs screening. The consequences of positive screening test is Amniocentesis which may harm the fetus. And in positive cases an abortion may be required.

97. BUT Good professionals should treat guidelines more as options. As True standards and professional organizations do not enforce adherence. Change in health care is possible with guidelines. Its creation and Implementation reflects the collaborative nature of health care.

98. Future Establish a culture of EBLM How ? Change the pattern of Journal Club – start from the Residents Evaluating a systemic review or Even journal can be even a part Of MD evaluation.

100. There are different checklists for different study Designs at: 1.The centre for Evidence Based Medicine ( WWW.cebm.net ) 2.Casp International network ( WWW.caspinternational.org.uk ) 3. Centre for Health Evidence ( WWW.cche.net )

101. Impact of EBLM

102. THANK YOU For your patient listening