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TRANSCRIPT
RATING QUALITY OF EVIDENCE AND STRENGTH OF RECOMMENDATIONS IN
GI USING THE GRADE FRAMEWORKAGA Clinical Practice & Quality Management Committee
Teleconference 17 Oct 2008
Yngve Falck-Ytter, M.D.Assistant Professor of Medicine
Case Western Reserve University, ClevelandDivision of Gastroenterology, Case and VA Medical Center
Disclosure
In the past 4 years, Dr. Falck-Ytter received no personal payments for services from industry. His research group received research grants from 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.
Content
Background and rationale for revisiting guideline methodology
The GRADE approach
Grading the quality of evidence and strength of recommendations in GI
Hierarchy of evidence
STUDY DESIGN Randomized Controlled
Trials Cohort Studies and
Case Control Studies Case Reports and Case
Series, Non-systematic observations
BIAS
Expert Opinion
Exp
ert O
pin
ion
Expert Opinion
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 fulfill needs
Change practitioner behavior However, wide variation in
approachesGRADE working group. BMJ. 2004 & 2008
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Grading used in GI CPGsAASLD AGA ACG ASGE
I RCTs I RCTs, well designed, n↑ for suff. stat. power
I Syst. review of RCTs
A. Prospect. controlled trials
II-1 Controlled trials(no randomization)
II 1 large well-designed clinical trial (+/- rand.), cohort or case-control studies or well designed meta-analysis
II-3 Multiple time series, dramatic uncontr. experiments
III Opinion of respected authorities, descrip. epidemiology
II-2 Cohort or case-control analytical studies
III Clinical experience, descr. studies, expert comm.
IV Not rated
II 1+ properly desig. RCT, n↑, clinical setting
III Publ., well-desig. trials, pre-post, cohort, time series, case-control studies
IV Non-exp. studies >1 center/group, opinion respected authorities, clinical evidence, descr. studies, expert consensus comm.
B. Obser-vational studies
C. Expert opinion
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
GRADE Working GroupDavid 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 ProfessorGillian 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, UKHelena 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, USAc) Centers for Disease Control and Prevention, USAd) University of Newcastle upon Tyne, UKe) German Cochrane Centre, Germanyf) Norwegian Centre for Health Services, Norwayg) McMaster University, Canadah) Scottish Intercollegiate Guidelines Network, UKi) Fédération Nationale des Centres de Lutte Contre le Cancer, Francej) University of Newcastle, Australiak) McMaster University, Canadal) National Institute for Clinical Excellence, UKm) Università di Modena e Reggio Emilia, Italyn) Centro per la Valutazione della Efficacia della Assistenza Sanitaria, Italyo) Australasian Cochrane Centre, Australia p) Polish Institute for Evidence Based Medicine, Polandq) The Cancer Council, Australiar) Centre for Evidence-based Medicine, UKs) National Cancer Institute, Italyt) World Health Organisation, Switzerland u) Finnish Medical Society Duodecim, Finland v) Duke University Medical Center, USA w) Centers for Disease Control and Prevention, USAx) University of London, UKY) BMJ Clinical Evidence, UK
GRADE uptake
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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 particular recommendation.
Although the degree of confidence is a continuum, we suggest using four categories:
High Moderate Low Very low
I B II V III
Quality of evidence across studies
Outcome #1Outcome #2Outcome #3
Quality: HighQuality: ModerateQuality: Low
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
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What is the study design?
1. Design and execution
Study limitations (risk of bias) Lack of allocation concealment No true intention to treat principle Inadequate blinding Loss to follow-up Early stopping for benefit
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 17
Heterogeneity
3. Directness of Evidence
Indirect comparisons Interested in head-to-head comparison Drug A versus drug B Infliximab versus adalimumab in Crohn’s
disease
Differences in patients (early cirrhosis vs end-stage cirrhosis) interventions (CRC screening: flex. sig. vs
colonoscopy) outcomes (non-steroidal safety: ulcer on
endoscopy vs symptomatic ulcer complications)
4. Imprecision
Small sample size small number of events wide confidence intervals uncertainty about magnitude of effect
5. Reporting Bias (Publication Bias)
Reporting of studies publication bias
number of small studies Reporting of outcomes
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Quality assessment criteria
Lower if…Quality of evidence
High (4)
Moderate (3)
Low (2)
Very low (1)
Study limitations(design and execution)
Inconsistency
Indirectness
Imprecision
Publication bias
Observational study
Study design
Randomized trial
Higher if…
What can raise the quality of evidence?
BMJ 2003;327:1459–61 22
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Quality assessment criteria
Lower if… Higher if…Quality of evidence
High (4)
Moderate (3)
Low (2)
Very low (1)
Study design
Randomized trial
Observational study
Study limitations
Inconsistency
Indirectness
Imprecision
Publication bias
Large effect (e.g., RR 0.5)Very large effect (e.g., RR 0.2)
Evidence of dose-response gradient
All plausible confounding would reduce a demonstrated effect
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Categories of quality
LowFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Further research is very unlikely to change our confidence in the estimate of effectHigh
ModerateFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Very low Any estimate of effect is very uncertain
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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
GRADE evidence profile
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 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
Determinants of the strength of recommendation
Factors that can weaken the strength of a recommendation
Explanation
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.
Developing recommendations
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 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
Where GRADE fits inPrioritize 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 findingsAssess 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
GR
AD
E
Systematic review
Guideline development
PICO
OutcomeOutcomeOutcomeOutcome
Formulate
question
Rate
importa
nce
Critical
Important
Critical
Not important
Create
evidence
profile with
GRADEpro
Summary of findings & estimate of effect for each outcome
Rate overall quality of
evidence across outcomes based
on lowest quality of critical outcomes
Panel
RCT start high, obs. data start
low1. Risk of bias2. Inconsisten
cy3. Indirectnes
s4. Imprecision5. Publication
bias
Gra
de
dow
nG
rad
e
up
1. Large effect
2. Dose response
3. Confounders
Rate quality
of evidence
for each
outcomeSelect
outcomes
Very low
LowModerate
High
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)
• “We recommend using…”• “We suggest using…”• “We recommend against using…”• “We suggest against using…”
Outcomes
across
studies
Conclusions
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 Transparency in decision making and
judgments is key