Rating the Evidence: Using GRADE to Develop Clinical Practice Guidelines (Text Version)

On September 14, 2009, Yngve Falck-Ytter and Holger Schüenemann made this presentation at the 2009 Annual Conference. Select to access the PowerPoint® presentation (4.6 MB). Plugin Software Help.

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Rating the Evidence: Using GRADE to Develop Clinical Practice Guidelines

AHRQ Annual Meeting 2009:
"Research to Reform: Achieving Health System Change"

September 14, 2009

Yngve Falck-Ytter, M.D.
Case Western Reserve University, Cleveland, Ohio

Holger Schüenemann, M.D., Ph.D.
Chair, Department of Clinical Epidemiology & Biostatistics
Michael Gent Chair in Healthcare Research
McMaster University, Hamilton, Canada

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Disclosure

In the past 5 years, Dr. Falck-Ytter received no personal payments for services from industry. His research group received research grants from Three Rivers, Valeant and Roche that were deposited into non-profit research accounts. He is a member of the GRADE working group which has received funding from various governmental entities in the US and Europe. Some of the GRADE work he has done is supported in part by grant # 1 R13 HS016880-01 from the Agency for Healthcare Research and Quality (AHRQ).

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Content

• Part 1
  • Introduction
• Part 2
  • Why revisiting guideline methodology?
• Part 3
  • The GRADE approach
    • Quality of evidence
• Part 4
  • The GRADE approach
    • Strength of recommendations

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Q to audience

• Involved in giving recommendations?
• • Using any form of grading system?
• Familiarity with GRADE:
• • Heard about GRADE before this conference?
  • Read a GRADE article published by the GRADE working group?
  • Attended a GRADE presentation?
  • Attended a hands-on GRADE workshop?

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Reassessment of clinical practice guidelines

• Editorial by Shaneyfelt and Centor (JAMA 2009)
• • "Too many current guidelines have become marketing and opinion-based pieces."
  • "AHA CPG: 48% of recommendations are based on level C = expert opinion."
  • ".clinicians do not use CPG [.] greater concern [.] some CPG are turned into performance measures."
  • "Time has come for CPG development to again be centralized, e.g., AHQR."

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Evidence-based clinical decisions

Diagram of three interlocking circles representing:

• Clinical state and circumstances
• Patient values and preferences
• Research evidence

The word "Expertise" is superimposed over the circles and "Equal for all" is below it.

Haynes et al. 2002

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Before GRADE

Arrows point from cell "I" to cells "A" and "B."

Oxford Centre of Evidence Based Medicine; http://www.cebm.net

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Where GRADE fits in

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GRADE uptake

A collage of many different logos.

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GRADE—
Why revisiting guideline methodology?
 

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Disclosure

Dr. Schüenemann receives no personal payments for service from the pharmaceutical industry. The research group he belongs to received research grants from the industry that are deposited into research accounts.
Institutions or organizations that he is affiliated with likely receive funding from for-profit sponsors that are supporting infrastructure and research that may serve his work.
He is documents editor for the American Thoracic Society and co-chair of the GRADE Working Group.

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Content

• Why grading
• Confidence in information and recommendations
• Intro to:
• • Quality of evidence
  • Strength of recommendations

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Please discuss the difference between consensus statements and guidelines?

Be prepared to discuss your answer

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There are no RCTs!

• Do you think that users of recommendations would like to be informed about the basis (explanation) for a recommendation or coverage decision if they were asked (by their patients)?
• I suspect the answer is "yes"
• If we need to provide the basis for recommendations, we need to say whether the evidence is good or not so good; in other words perhaps "no RCTs"

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Hierarchy of evidence

• STUDY DESIGN
• • Randomized Controlled Trials
  • Cohort Studies and Case Control Studies
  • Case Reports and Case Series, Non-systematic observations

A diagram of a pyramid with "BIAS" written at the top and "Expert Opinion" at the bottom.

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Confidence in evidence

• There always is evidence
  • "When there is a question there is evidence"
• Better research >> greater confidence in the evidence and decisions

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Who can explain the following?

• Concealment of randomization
• Bias, confounding and effect modification
• Blinding (who is blinded in a double blinded trial?)
• Intention to treat analysis and its correct application
• Why trials stopped early for benefit overestimate treatment effects?
• P-values and confidence intervals

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Hierarchy of evidence

• STUDY DESIGN
• • Randomized Controlled Trials
  • Cohort Studies and Case Control Studies
  • Case Reports and Case Series, Non-systematic observations
  • Expert Opinion

A diagram of a pyramid with "BIAS" written at the top and "Expert Opinion" at the bottom.

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Reasons for grading evidence?

• Appraisal of evidence has become complex and daunting
• People draw conclusions about the
• • Quality of evidence and strength of recommendations
• Systematic and explicit approaches can help
• • Protect against errors, resolve disagreements
  • Communicate information and fulfil needs
• Change practitioner behavior
• However, wide variation in approaches

GRADE working group. BMJ. 2004 & 2008

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Which grading system?

Recommendation for use of oral anticoagulation in patients with atrial fibrillation and rheumatic mitral valve disease
 

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What to do?

Graphic image of a doctor and a photo of a large grouping of traffic signal lights.

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Recommendations vs statements!

Other options are available but not recommended for routine use as initial or first-line controllers in Step 2. Sustained-release theophylline has only weak anti-inflammatory and controller efficacy 126-130 (Evidence B) and is commonly associated with side effects that range from trivial to intolerable 131-132. Cromones (nedocromil sodium and sodium cromoglycate) have comparatively low efficacy, though a favorable safety profile 133-136 (Evidence A).

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Limitations of older systems & approaches

• Confuse quality of evidence with strength of recommendations

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Levels of evidence

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Recommendations

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Limitations of older systems & approaches

• Confuse quality of evidence with strength of recommendations
• Lack well-articulated conceptual framework
• Criteria not comprehensive or transparent
• Focus on single outcomes

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GRADE Quality of Evidence

• In the context of a systematic review
  • The quality of evidence reflects the extent to which we are confident that an estimate of effect is correct.
• In the context of making recommendations
  • The quality of evidence reflects the extent to which our confidence in an estimate of the effect is adequate to support a particular recommendation.

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What makes you confident in health care decisions

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Confident in the evidence?

A meta-analysis of observational studies showed that bicycle helmets reduce the risk of head injuries in cyclists.
OR: 0.31, 95%CI: 0.26 to 0.37

A meta-analysis of observational studies showed that warfarin prophylaxis reduces the risk of thromboembolism in patients with cardiac valve replacement.
RR: 0.17, 95%CI: 0.13 to 0.24

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No titles

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GRADE: Quality of evidence

• The extent to which our confidence
  in an estimate of the treatment effect
  is adequate to support a particular recommendation.
• GRADE defines 4 categories of quality:
  • High
  • Moderate
  • Low
  • Very low

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Quality of evidence across studies

Diagram of several studies showing quality outcomes of high, moderate and low.

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Determinants of quality

• RCTs start high
• Observational studies start low

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What is the study design?

1: Rev Esp Enferm Dig. 1998 Nov;90(11):788-93

Surgical treatment of the acute cholecystitis in the laparoscopic age. A comparative study: laparoscopic against laparatomy.

[Article in English, Spanish]

Carbajo Caballero MA, Martin del Olmo JC, Blanco Alvarez JI, Cuesta de la Llave C. Atienza Sanchez R, Inglada Daliana L, Vaquero Puerta C.

Department of Surgery, Medina del Campo Hospital, Valladolid, Spain.

OBJECTIVE: The aim of this study was to assess the complications and results of the laparoscopic opposite to open treatment of the acute choecystitis. METHODS: A retrospective randomized study with two groups of 30 patients each one. The parameters tested were age, sex, risk factors, surgical time, hospital stay, cholecystitis tyep, and early or late complications. RESULTS: In the two groups there were no significant differences in age, sex, risk factors, type of cholecystitis and surgical time. The average of hospital stay was significantly longer for open cholecystectomy (9.5) than for laparoscopic technique (2.30) (p < 0.001). The complication rate was higher (7.30%) in open cholecystectomy. CONCLUSIONS: The laparoscopic cholecystectomy should be the standard procedure for the treatment of the acute cholecystitis.

The words "METHODS: A retrospective randomized study" are highlighted.

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Determinants of quality

What lowers quality of evidence? 5 factors:

• Methodological limitations
• Inconsistency of results
• Indirectness of evidence
• Imprecision of results
• Publication bias

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Methodological limitations

Assessment of detailed design and execution (risk of bias)

• For RCTs:
• • Lack of allocation concealment
  • No true intention to treat principle
  • Inadequate blinding
  • Loss to follow-up
  • Early stopping for benefit

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Allocation concealment

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5 vs 4 chemo-Rx cycles for AML

Hazard ratio plot of mortality in the five versus four courses randomization in the MRC AML12 trials.

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Studies stopped early becasue of benefit

Hazard ratio plot of mortality in the five versus four courses randomization in the MRC AML12 trials.

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What about scoring tools?

Max 5 points for quality

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Cochrane Risk of bias graph in RevMan 5

Example of a "Risk of bias graph"

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Inconsistency of results

• Look for explanation for inconsistency
  • Patients, intervention, comparator, outcome, methods
• Judgment
  • Variation in size of effect
  • Overlap in confidence intervals
  • Statistical significance of heterogeneity
  • I2

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Heterogeneity

Chart showing neurological or vascular complications or death within 30 days of endovascular treatment (stent, balloon angioplasty) vs. surgical carotid endarterectomy (CEA)
 

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Indirectness of evidence

• Indirect comparisons
  • Interested in head-to-head comparison
  • Drug A versus drug B
  • Tenofovir versus entecavir in hepatitis B treatment
• Differences in
  • Patients (early cirrhosis vs end-stage cirrhosis)
  • Interventions (CRC screening: flex. sig. vs colonoscopy)
  • Comparator (e.g., differences in dose)
  • Outcomes (non-steroidal safety: ulcer on endoscopy vs symptomatic ulcer complications)

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Imprecision of results

• Small sample size
  • Small number of events
  • Wide confidence intervals
  • Uncertainty about magnitude of effect

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Imprecision

Chart showing any stroke (or death) within 30 days of endovascular treatment (stent, balloon angioplasty) vs. surgical carotid endarterectomy (CEA)
 

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Publication bias

• Reporting of studies
  • Publication bias
  • • Number of small studies

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All phase II and III licensing trial for antidepressant drugs between 1987 and 2004 (74 trials—23 were not published)

Two charts showing Journal and FDA estimates.

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Quality assessment criteria

What can raise the quality of evidence?

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Photo of an x-ray.

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Quality assessment criteria

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Conceptualizing quality

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Process flow

Graphic showing process flow including:

• Clinical question
• Rate importance
• Select outcomes
• Quality rating outcomes across studies

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GRADE evidence profile

Example of a Quality Assessment.

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GRADE—From evidence to decisions

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Strength of recommendations

• Desirable effects
• • Health benefits
  • Less burden
  • Savings
• Undesirable effects
• • Harms
  • More burden
  • Costs

Slide 57

Developing recommendations

Figure describing the balance between important benefits and downsides related to a recommendation. The process begins by evaluating whether desirable effects outweigh undersirable effects or vice versa. Moving on to making a recommendation requires a decision: if the balance is clear, a strong recommendation for or against an action follows. If the balance is not clear, a weak recommendation for or against an action follows. Widely differing values can also lead to a less clear balance of benefits versus downsides.

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Strength of recommendation

• "The strength of a recommendation reflects the extent to which we can, across the range of patients for whom the recommendations are intended, be confident that desirable effects of a management strategy outweigh undesirable effects."
• Strong or weak/conditional

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Quality of evidence & strength of recommendation

• GRADE separates quality of evidence from strength of recommendation
• Linked but no automatism
• Other factors beyond the quality of evidence influence our confidence that adherence to a recommendation causes more benefit than harm

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What makes Guidelines Evidence-Based in 2009?

Standardized Reporting of Clinical Practice Guidelines: A Proposal from the Conference on Guideline Standardization
Checklist for reporting: 18 items

14. Recommendations and rationale—state the recommended action precisely. Indicate the quality of evidence and the recommendation strength.

Ann Intern Med. 2003

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What makes Guidelines Evidence-Based in 2009?

Standardized Reporting of Clinical Practice Guidelines: A Proposal from the Conference on Guideline Standardization
Checklist for reporting: 18 items

16. Patient preferences—describe the role of patient preferences when a recommendation involves a substantial element of personal choice or values.

Ann Intern Med. 2003

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A COPD guideline—do you want your review used like this?

7.6. Mucolytic/antioxidant therapy

• These include drugs such as:
• • Ambroxol
  • Erdosteine
  • Carbocysteine
  • Iodinated glycerol

The regular use of these drugs has been evaluated in a number of studies with little evidence of any effect on lung function.

Data from a Cochrane review of the studies supports a role for these drugs in reducing the number of exacerbations of chronic bronchitis [33].

There is better evidence that N-acetylcysteine, a drug with mucolytic and anti-oxidant actions, can reduce the number of exacerbations of COPD and this is currently under study in a large prospective trial [34].

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Another COPD guideline

Mucolytic (mucokinetic, mucoregulator) agents (ambroxol, erdosteine, carbocysteine, iodinated glycerol). The regular use of mucolytics in COPD has been evaluated in a number of long-term studies with controversial results. Although a few patients with viscous sputum may benefit from mucolytics, the overall benefits seem to be very small, and the widespread use of these agents cannot be recommended at present.

Antioxidan agents. Antioxidants, in particular N-acetylcysteine, have been reported in small studies to reduce the frequency of exacerbations, leading to speculation that these medications could have a role in the treatment of patients with recurrent exacerbations. However, a large randomized controlled trial found no effect of N-acetylcysteine on the frequency of exacerbations, except in patients not treated with inhaled glucocorticosteroids.

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And another COPD guideline

1.2.14 Mucolytic therapy
1.2.14.1 Mucolytic drug therapy should be considered in patients with a chronic cough productive of sputum. B
1.2.14.2 Mucolytic therapy should be continued if there is symptomatic improvement (for example, reduction in frequency of cough and sputum production). D

1.2.15 Anti-oxidant therapy
1.2.15.1 Treatment with alpha-tocopherol and beta-carotene supplements, alone or in combination, is not recommended. A

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What to do?

Graphic image of a doctor and a photo of a large grouping of traffic signal lights.

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Current state of recommendations

Photo of the International Journal of Medical Informatics titled "The Yale Guideline Recommendation Corpus: A representative sample of the knowledge content of guidelines"

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Current state of recommendations

• Reviewed 7527 recommendations
• • 1275 randomly selected
• Inconsistency across/within
• 31.6% did not recommendations clearly
• • Most of them not written as executable actions
• 52.7% did not indicated strength

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Yale Guideline Corpus

1. Identify the critical recommendations in guideline text using semantic indicators
2. Use consistent semantic and formatting indicators throughout the publication
3. Group recommendations together in a summary section
4. Do not use assertions of fact as recommendations.
5. Clearly and consistently assign evidence quality and recommendation strength in proximity
6. • Distinguish between the distinct concepts of quality of evidence and strength of recommendation.

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Challenges in wording recommendations

• Need to express (two) levels
• Need to express direction
• Differences across languages
• Need codes (letters, symbols, numbers)

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Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations

Photo of a clipping titled "Letters, numbers, symbols and words: how to communicate grades of evidence and recommendations" with highlighted text:

We did not find any studies comparing different systems of communicating grades in health care. A number of studies have compared alternative ways of presenting information about risk, but none addressed the use of codes and grades.

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Categories of recommendations

• Although the degree of confidence is a continuum, we suggest using two categories: strong and weak/conditional.
• Strong recommendation: the panel is confident that the desirable effects of adherence to a recommendation outweigh the undesirable effects.
• Weak recommendation: the panel concludes that the desirable effects of adherence to a recommendation probably outweigh the undesirable effects, but is not confident.

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Implications of a strong recommendation

• Patients: Most people in your situation would want the recommended course of action and only a small proportion would not
• Clinicians: Most patients should receive the recommended course of action
• Policy makers: The recommendation can be adapted as a policy in most situations

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Implications of a weak/conditional recommendation

• Patients: The majority of people in your situation would want the recommended course of action, but many would not
• Clinicians: Be prepared to help patients to make a decision that is consistent with their own values
• Policy makers: There is a need for substantial debate and involvement of stakeholders

Slide 74

Case scenario

A 13 year old girl who lives in rural Indonesia presented with flu symptoms and developed severe respiratory distress over the course of the last 2 days. She required intubation. The history reveals that she shares her living quarters with her parents and her three siblings. At night the family's chicken stock shares this room too and several chicken had died unexpectedly a few days before the girl fell sick.

Interventions: antivirals, such as neuraminidase inhibitors oseltamivir and zanamivir

Slide 75

Relevant healthcare question?

• Clinical question:
  • Population: Avian Flu/influenza A (H5N1) patients
  • Intervention: Oseltamivir (or Zanamivir)
  • Comparison: No pharmacological intervention
  • Outcomes: Mortality, hospitalizations, resource use, adverse outcomes, antimicrobial resistance

WHO Avian Influenza GL. Schunemann et al., The Lancet ID, 2007

Slide 76

How would you make decisions?

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Judgments about the strength of a recommendation

• No precise threshold for going from a strong to a weak recommendation
• The presence of important concerns about one or more of these factors make a weak recommendation more likely.
• Panels should consider all of these factors and make the reasons for their judgements explicit.
• Recommendations should specify the perspective that is taken (e.g. individual patient, health system) and which outcomes were considered (including which, if any costs).

Slide 78

Evidence Profile

Oseltamivir for treatment of H5N1 infection:

Example of a Quality Assessment.

Slide 79

Oseltamivir for Girl with Avian Flu

• Summary of findings:
  • No clinical trial of oseltamivir for treatment of H5N1 patients.
  • 4 systematic reviews and health technology assessments (HTA) reporting on 5 studies of oseltamivir in seasonal influenza.
    • Hospitalization: OR 0.22 (0.02—2.16)
    • Pneumonia: OR 0.15 (0.03 —0.69)
  • 3 published case series.
  • Many in vitro and animal studies.
  • No alternative that is more promising at present.
  • Cost: ~ $45 per treatment course

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What are the factors that determine your decisions?

Slide 81

GRADE: Factors influencing decisions and recommendations

• Quality of Evidence
• Balance of desirable and undesirable consequences
• Values and preferences
• Cost

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Determinants of the strength of recommendation

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Determinants of the strength of recommendation

Table. Decisions about the strength of a recommendation
Frequent "yes" answers will increase the likelihood of a weak recommendation

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Oseltamivir—Avian Influenza

Frequent "yes" answers will increase the likelihood of a weak recommendation

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Example: Oseltamivir for Avian Flu

Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (????? recommendation, very low quality evidence).

Schunemann et al. The Lancet ID, 2007

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Are values important? Should resources be considered?

Slide 87

Example: Oseltamivir for Avian Flu

Recommendation: In patients with confirmed or strongly suspected infection with avian influenza A (H5N1) virus, clinicians should administer oseltamivir treatment as soon as possible (strong recommendation, very low quality evidence).

Values and Preferences
Remarks: This recommendation places a high value on the prevention of death in an illness with a high case fatality. It places relatively low values on adverse reactions, the development of resistance and costs of treatment.

Schunemann et al. The Lancet ID, 2007

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Other explanations

Remarks: Despite the lack of controlled treatment data for H5N1, this is a strong recommendation, in part, because there is a lack of known effective alternative pharmacological interventions at this time.

The panel voted on whether this recommendation should be strong or weak and there was one abstention and one dissenting vote.

Slide 89

Health Care Question (PICO) Systematic reviews

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Process flow diagrams

Diagrams showing the process flows of the Systematic review and the Guideling development.

Slide 91

No titles

Slide 92

Ideal vs. practical ad hoc GRADE approaches

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Evidence-based guidelines?

• What is evidence?

Slide 94

What is evidence?

• a: An outward sign, an indication
• b: Something that furnishes proof