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Adopting the GRADE approach for clinical practice guidelines in gastroenterology – benefits and challenges. AGA Practice Guidelines Committee Meeting, Chicago May 31, 2009 Yngve Falck-Ytter, M.D. Assistant Professor of Medicine Case Western Reserve University

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Adopting the GRADE approach for clinical practice guidelines in gastroenterology – benefits and challenges

AGA Practice Guidelines Committee Meeting, Chicago

May 31, 2009

Yngve Falck-Ytter, M.D.

Assistant Professor of Medicine

Case Western Reserve University

Director of Hepatology, VA Medical Center


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).


Part 1

  • Why revisiting guideline methodology?

  • GRADE approach

    • Quality of evidence

    • Strength of recommendations

  • Why societies have adopted GRADE

Content continued
Content (continued)

Part 2 – practical consideration

  • Ideal vs. practical ad hoc approaches

  • Funding guideline work

Reassessment of clinical practice guidelines
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…”

Evidence based clinical decisions
Evidence-based clinical decisions

Clinical state and circumstances

Patient values and preferences


Research evidence

Equal for all

Haynes et al. 2002

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

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 to

    • protect against errors, resolve disagreements

    • communicate information and fulfill needs

    • be transparent about the process

  • Change practitioner behavior

  • However, wide variation in approaches

GRADE working group. BMJ. 2004 & 2008

Which grading system
Which grading system?

P: In patients with acute hepatitis C …I : Should anti-viral treatment be used … C: Compared to no treatment …

O: To achieve viral clearance?





Class I

AASLD (2009)



VA (2006)



SIGN (2006)


“Most authorities…”

AGA (2006)

Scenario 2
Scenario (2)

Should patients with risk factors for viral hepatitis be screened with a hepatitis C antibody (ELISA) test to identify patients with past hepatitis C exposure?

Level of evidence in gi cpgs
Level of evidence in GI CPGs





1. Multiple published, well-controlled (?) randomized trials or a well designed systemic (?) meta-analysis

AMultiple RCTs or meta-analysis


GoodConsistent, well-designed, well conducted studies […]

B. RCT with important limitations

BSingle randomized trial, or non-randomized studies

FairLimited by the number, quality or consistency of individual studies […]

2. One quality-published (?) RCT, published well-designed cohort/ case-control studies

C. Obser-vational studies

3. Consensus of authoritative (?) expert opinions based on clinical evidence or from well designed, but uncontrolled or non-rand. clin. trials

C Only consensus opinion of experts, case studies, or standard-of-care

Poor… important flaws, gaps in chain of evidence…

D. Expert opinion

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

  • Grades of Recommendation Assessment, Development and Evaluation

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

Where grade fits in
Where GRADE fits in

Prioritize problems, establish panel

Systematic review

Searches, selection of studies, data collection and analysis

Assess the relative importance of outcomes

Prepare evidence profile: Quality of evidence for each outcome and summary of findings


Assess overall quality of evidence

Decide direction and strength of recommendation

Draft guideline

Consult with stakeholders and / or external peer reviewer

Disseminate guideline

Implement the guideline and evaluate

Grade quality of evidence
GRADE: Quality of evidence

The extent to which our confidence in an estimate of the treatment effect is adequate to support particular recommendation.

Although the degree of confidence is a continuum, we suggest using four categories:

  • High

  • Moderate

  • Low

  • Very low

Quality of evidence across studies
Quality of evidence across studies

Outcome #1

Quality: High

Outcome #2

Quality: Moderate

Outcome #3

Quality: Low





Determinants of quality
Determinants of quality

  • RCTs start high

  • Observational studies start low

  • What lowers quality of evidence? 5 factors:

    • Detailed design and execution

    • Inconsistency of results

    • Indirectness of evidence

    • Imprecision

    • Publication bias

1 design and execution
1. Design and execution

  • Study limitations (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

      For observational studies:

    • Selection

    • Comparability

    • Exposure/outcome

Allocation concealment
Allocation concealment

250 RCTs out of 33 meta-analysesAllocation concealment: Effect (Ratio of OR)

adequate 1.00 (Ref.)

unclear 0.67 [0.60 – 0.75]

not adequate 0.59 [0.48 – 0.73]


  • * significant

Schulz KF et al. JAMA 1995

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


Pagliaro L et al. Ann Intern Med 1992;117:59-70

3 directness of evidence
3. Directness 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)

4 imprecision
4. Imprecision

Small sample size

  • small number of events

  • wide confidence intervals

  • uncertainty about magnitude of effect


appreciable benefit

appreciable harm







5 reporting bias publication bias
5. Reporting Bias (Publication Bias)

  • Reporting of studies

    • publication bias

      • number of small studies

  • Reporting of outcomes

Quality assessment criteria

Study design

Lower if…

Higher if…

Quality of evidence

Randomized trial

Study limitations

(design and execution)

High (4)

Moderate (3)


What can raise the quality of evidence?

Observational study

Low (2)


Very low (1)


Publication bias

Quality assessment criteria

Lower if…

Higher if…

Quality of evidence

Study design

Study limitations

Large effect (e.g., RR 0.5)

Very large effect (e.g., RR 0.2)

High (4)

Randomized trial

Moderate (3)


Evidence of dose-response gradient

Observational study

Low (2)


All plausible confounding would reduce a demonstrated effect

Very low (1)


Publication bias

Categories of quality
Categories of quality


Further research is very unlikely to change our confidence in the estimate of effect


Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate


Very low

Any estimate of effect is very uncertain

Judgments about the overall quality of evidence
Judgments about the overall quality of evidence

  • Most systems not explicit

  • Options:

    • Benefits

    • Primary outcome

    • Highest

    • Lowest

  • Beyond the scope of a systematic review

  • GRADE: Based on lowest of all the critical outcomes

Going from evidence to recommendations
Going from evidence to recommendations

  • Deliberate separation of quality of evidence from strength of recommendation

  • No automatic one-to-one connection as in other grading systems

  • Example: What if there is high quality evidence, but the balance between benefit and risks are finely balanced?

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.”

Although the strength of recommendation is a continuum, we suggest using two categories :

“Strong” and “Weak”

Desirable and undesirable effects
Desirable and undesirable effects

  • Desirable effects

    • Mortality reduction

    • 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

4 determinants of the strength of recommendation
4 determinants of the strength of recommendation

Factors that can weaken the strength of a recommendation


  • Lower quality evidence

The higher the quality of evidence, the more likely is a strong recommendation.

  • Uncertainty about the balance of benefits versus harms and burdens

The larger the difference between the desirable and undesirable consequences, the more likely a strong recommendation warranted. The smaller the net benefit and the lower certainty for that benefit, the more likely is a weak recommendation warranted.

  • Uncertainty or differences in values

The greater the variability in values and preferences, or uncertainty in values and preferences, the more likely weak recommendation warranted.

  • Uncertainty about whether the net benefits are worth the costs

The higher the costs of an intervention – that is, the more resources consumed – the less likely is a strong recommendation warranted.

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

6 main misconceptions
6 main misconceptions

  • Isn’t GRADE expensive to realize?

  • Isn’t GRADE more complicated, takes longer and requires more resources?

  • Isn’t GRADE eliminating the expert ?

  • But what about mechanism of disease, diagnosis, cost?

  • But GRADE does not have an “insufficient evidence to make recommendation” category! (or: the “optional” category), no?

  • But we only “recommend” – we can’t possibly give weak recommendations!


evidence profile with GRADEpro

Summary of findings & estimate of effect for each outcome

Guideline development


overall quality of evidence

across outcomes based on lowest quality

of critical outcomes

Rate quality of evidence for each outcome

Outcomes across studies

Formulate question

Rate importance

Select outcomes

RCT start high,

obs. data start low

Risk of bias




Publication bias











Grade down




Very low




Large effect

Dose response


Grade up


  • Formulate recommendations:

  • For or against (direction)

  • Strong or weak (strength)

    • By considering:

    • Quality of evidence

    • Balance benefits/harms

    • Values and preferences

  • Revise if necessary by considering:

  • Resource use (cost)

Systematic review

  • “We recommend using…”

  • “We suggest using…”

  • “We recommend against using…”

  • “We suggest against using…”

Summary and why institutions adopt grade
Summary, andWhy institutions adopt GRADE

  • GRADE is gaining acceptance as international standard

  • GRADE has criteria for evidence assessment across a range of questions and outcomes

  • Criteria for moving from evidence to recommendations

  • Simple, transparent, systematic

  • Balance between simplicity and methodological rigor

Ideal vs practical ad hoc grade approaches
Ideal vs. practical ad hoc GRADE approaches






Systematic review

GRADE eTables

Qual. of evidence

Strength of rec.

Follows int. standards

Methodolog. most rigorous

Easily maintainable

Fully transparent process

Access to methodologist

Access to evidence centers

Initially more resource intensive, long-term savings


Ad hoc review

GRADE eTables

Qual. of evidence

Strength of rec.

Still retaining major advantages of the of the “ideal approach”

Risk of bias higher

Access methodologist rec.

Only minimal addl. cost


Ad hoc review

GRADE eTables

Qual. of evidence

Strength of rec.

Option to fully “upgrade” to an “ideal approach”

Foundation of a methodo-logically sound system

Risk of bias higher

Access methodologist prn

No additional cost