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Holger Schünemann Yngve Falck-Ytter AHRQ Annual Conference Washington, September 8, 2008. GRADE Introduction. Disclosure.

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holger sch nemann yngve falck ytter ahrq annual conference washington september 8 2008
Holger Schünemann

Yngve Falck-Ytter

AHRQ Annual Conference

Washington, September 8, 2008

GRADE Introduction


In the past three years, Dr. Schünemann received no personal payments for service from the pharmaceutical industry. His research group received research grants and - until April 2008 - fees and/or honoraria that were deposited into research accounts from Chiesi Foundation and Lily, as lecture fees related to research methodology. He is documents editor for the American Thoracic Society. 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.

  • Background and rationale for revisiting guideline methodology
  • GRADE approach
    • Quality of evidence
    • Strength of recommendations
  • Background and rationale for revisiting guideline methodology
  • GRADE approach
    • Quality of evidence
    • Strength of recommendations
confidence in evidence
Confidence in evidence
  • There always is evidence
    • “When there is a question there is evidence”
  • Evidence alone is never sufficient to make a clinical decision
  • Better research  greater confidence in the evidence and decisions
hierarchy of evidence
Hierarchy of evidence
  • Randomized Controlled Trials
  • Cohort Studies and Case Control Studies
  • Case Reports and Case Series, Non-systematic observations


Expert Opinion

Expert Opinion

Expert Opinion

can you explain the following
Can you explain the following?
  • Concealment of randomization
  • 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
hierarchy of evidence1
Hierarchy of evidence
  • Randomized Controlled Trials
  • Cohort Studies and Case Control Studies
  • Case Reports and Case Series, Non-systematic observations


Expert Opinion

reasons for grading evidence
Reasons for grading evidence?
  • 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

which grading system
Evidence Recommendation

B Class I

A 1






Which grading system?

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

  • Background and rationale for revisiting guideline methodology
  • GRADE approach
    • Quality of evidence
    • Strength of recommendations
limitations of existing systems
Limitations of existing systems
  • confuse quality of evidence with strength of recommendations
  • lack well-articulated conceptual framework
  • criteria not comprehensive or transparent
  • GRADE unique
    • breadth, intensity of development process
    • wide endorsement and use
    • conceptual framework
    • comprehensive, transparent criteria
  • Focus on all important outcomes related to a specific question and overall quality
g rades of r ecommendation a ssessment d evelopment and e valuation
Grades of Recommendation Assessment, Development and Evaluation

GRADE Working Group

CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005, AJRCCM 2006, Chest 2006, BMJ 2008

grade working group
David Atkins, chief medical officera

Dana Best, assistant professorb

Martin Eccles, professord

Francoise Cluzeau, lecturerx

Yngve Falck-Ytter, associate directore

Signe Flottorp, researcherf

Gordon H Guyatt, professorg

Robin T Harbour, quality and information director h

Margaret C Haugh, methodologisti

David Henry, professorj

Suzanne Hill, senior lecturerj

Roman Jaeschke, clinical professork

Regina Kunx, Associate Professor

Gillian Leng, guidelines programme directorl

Alessandro Liberati, professorm

Nicola Magrini, directorn

James Mason, professord

Philippa Middleton, honorary research fellowo

Jacek Mrukowicz, executive directorp

Dianne O’Connell, senior epidemiologistq

Andrew D Oxman, directorf

Bob Phillips, associate fellowr

Holger J Schünemann, professorg,s

Tessa Tan-Torres Edejer, medical officert

David Tovey, Editory

Jane Thomas, Lecturer, UK

Helena Varonen, associate editoru

Gunn E Vist, researcherf

John W Williams Jr, professorv

Stephanie Zaza, project directorw

a) Agency for Healthcare Research and Quality,USA

b) Children's National Medical Center, USA

c) Centers for Disease Control and Prevention, USA

d) University of Newcastle upon Tyne, UK

e) German Cochrane Centre, Germany

f) Norwegian Centre for Health Services, Norway

g) McMaster University, Canada

h) Scottish Intercollegiate Guidelines Network, UK

i) Fédération Nationale des Centres de Lutte Contre le Cancer, France

j) University of Newcastle, Australia

k) McMaster University, Canada

l) National Institute for Clinical Excellence, UK

m) Università di Modena e Reggio Emilia, Italy

n) Centro per la Valutazione della Efficacia della Assistenza Sanitaria, Italy

o) Australasian Cochrane Centre, Australia

p) Polish Institute for Evidence Based Medicine, Poland

q) The Cancer Council, Australia

r) Centre for Evidence-based Medicine, UK

s) National Cancer Institute, Italy

t) World Health Organisation, Switzerland

u) Finnish Medical Society Duodecim, Finland

v) Duke University Medical Center, USA

w) Centers for Disease Control and Prevention, USA

x) University of London, UK

Y) BMJ Clinical Evidence, UK

GRADE Working Group
grade uptake
GRADE Uptake
  • World Health Organization
  • Allergic Rhinitis in Asthma Guidelines (ARIA)
  • American Thoracic Society
  • British Medical Journal
  • Infectious Disease Society of America
  • American College of Chest Physicians
  • UpToDate
  • American College of Physicians
  • Cochrane Collaboration
  • National Institute Clinical Excellence (NICE)
  • Infectious Disease Society of America
  • European Society of Thoracic Surgeons
  • Clinical Evidence
  • Agency for Health Care Research and Quality (AHRQ)
  • Over 20 major organizations
the grade approach
The GRADE approach

Clear separation of 2 issues:

1) 4 categories of quality of evidence: very low, low, moderate, or high quality?

  • methodological quality of evidence
  • likelihood of bias
  • by outcome

2) Recommendation: 2 grades - weak or strong (for or against)?

  • Quality of evidence only one factor


grade quality of evidence
GRADE Quality of Evidence

“Extent to which confidence in estimate of effect adequate to support decision”

  • high: considerable confidence in estimate of effect.
  • moderate: further research likely to have impact on confidence in estimate, may change estimate.
  • low: further research is very likely to impact on confidence, likely to change the estimate.
  • very low: any estimate of effect is very uncertain
determinants of quality
Determinants of quality
  • RCTs start high
  • observational studies start low
  • 5 factors lower the quality of evidence
    • detailed design and execution
    • inconsistency
    • indirectness
    • reporting bias
    • Imprecision
  • 3 factors can increase the quality of evidence
example design and execution
Example: Design and Execution
  • limitations
    • Randomization
    • lack of concealment
    • intention to treat principle violated
    • inadequate blinding
    • loss to follow-up
    • early stopping for benefit
design and execution
Design and Execution
  • From Cates , CDSR 2008

CDSR 2008

design and execution1
Design and Execution

Overall judgment required

2 consistency of results
2. Consistency 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
3 directness of evidence
3. Directness of Evidence
  • indirect comparisons
    • interested in A versus B
    • have A versus C and B versus C
  • differences in
    • patients
    • interventions
    • outcomes
4 reporting bias
4. Reporting Bias
  • reporting bias
    • reporting of studies
      • publication bias
        • number of small studies
    • reporting of outcomes

Example: a systematic review of topical treatments for seasonal allergic conjunctivitis showed that patients using topical sodium cromoglycate were more likely to perceive benefit than those using placebo. However, only small trials reported clinically and statistically significant benefits of active treatment, while a larger trial showed a much smaller and a statistically not significant effect (Owen 2004 [53]). These findings suggest that smaller studies demonstrating smaller effects might not have been published.

5 imprecision
5. Imprecision
  • small sample size
  • small number of events
    • wide confidence intervals
    • uncertainty about magnitude of effect
what can raise quality 3 factors
What can raise quality?3 Factors
  • large magnitude can upgrade one level
    • very large two levels
    • common criteria
      • everyone used to do badly
      • almost everyone does well
    • Epinephrin in allergic shock
  • dose response relation

(higher INR – increased bleeding)

  • Residual confounding unlikely to be responsible for observed effect
guideline development process1
Guideline development process

Summary of Findings


the clinical scenario
The clinical scenario

A 68 year old male long-term patient of yours. He suffers from COPD but is unable to stop smoking after over 30 years of tobacco use. He has been taking beta-carotene supplements for several months because someone in the “healthy food” store recommended it to prevent cancer.

He wants to know whether this will prevent him from getting cancer and whether he should use beta-carotene.

strength of recommendation
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.”
desirable and undesirable effects
Desirable and undesirable effects
  • Desirable effects
    • Mortality
    • improvement in quality of life, fewer hospitalizations/infections
    • reduction in the burden of treatment
    • reduced resource expenditure
  • Undesirable effects
    • deleterious impact on morbidity, mortality or quality of life, increased resource expenditure
implications of a strong recommendation
Implications of a strong recommendation
  • Patients: Most people in this 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
implications of a weak recommendation
Implications of a weak recommendation
  • Patients: The majority of people in this 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/decision aids and shared decision making
  • Policy makers: There is a need for substantial debate and involvement of stakeholders
the clinical question
The clinical question

Population: In smokers with COPD

Intervention: does beta-carotene suppl

Comparison: compared to no suppl.

Outcomes: reduce the risk of COPD symptoms, lung cancer

and death and improve PFTs?

two trials
Two trials

1) The Alpha-Tocopherol Beta-Carotene (ATBC) trial randomly assigned 29,133 people to receive beta carotene, tocopherol, both, or placebo.

Study participants averaged 57.2 years of age, 20.4 cigarettes per day, and 35.9 years of smoking. They were followed up for 5 to 8 years.

RR for lung cancer = 1.16 (95% CI 1.02-1.33)

Albanes et al, JNCI, 1996

two trials1
Two trials

2) The Beta-Carotene and Retinol Efficacy Trial (CARET) evaluated high-risk current and former smokers with a 20–pack-year history of smoking (n = 14,254), ~ 60 years old.

The participants were randomly assigned to receive either a combination of beta carotene and vitamin A or placebo. Mean length of follow up: 4 years.

RR for lung cancer = 1.28 (95% CI 1.04-1.57)

determinants of the strength of recommendation3
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

your recommendation
Your recommendation
  • Team up in pairs of two or three or four and formulate your recommendation for the guideline on COPD
  • I will collect your answers
our recommendation
Our recommendation

In patients with COPD who continue to smoke, we recommend stopping beta-carotene supplementation.


In patients with COPD who continue to smoke, clinicians should stop beta-carotene supplementation.

  • GRADE is gaining acceptance as international standard
  • Criteria for evidence assessment across questions and outcomes
  • Criteria for moving from evidence to recommendations
  • Simple, transparent, systematic
    • four categories of quality of evidence
    • two grades for strength of recommendations
  • Transparency in decision making and judgments is key