Transcript Clinical Epidemiology Boot Camp Systematic Reviews

Clinical Epidemiology Boot Camp:
Systematic Reviews
Selina Liu
MD MSc FRCPC Cert Endo
December 17, 2014
Outline

Introduction – Evidence-Based Medicine (EBM)


Levels of evidence
To discuss the definition of a systematic review

vs. traditional/narrative reviews

The process of conducting a systematic review
Strengths & limitations of systematic reviews


To describe how to critically appraise a systematic review

Example of a systematic review
Evidence-Based Medicine

What is Evidence-Based Medicine?

“…the conscientious, explicit and judicious use of current best
evidence in making decisions about the care of individual
patients”

“ It’s about integrating individual clinical expertise and the best
external evidence”

philosophical origins – date back to mid-19th century Paris (or
possibly earlier)
Sackett DL et al. BMJ. 1996;312(7023):71-2
Evidence-Based Medicine

Five Steps of Evidence-Based Medicine

1. Asking Focused Questions


2. Finding the Evidence


Testing evidence for validity, clinical relevance, and applicability
4. Making a Decision


Systematic retrieval of the best evidence available
3. Critical Appraisal


Translation of uncertainty to an answerable question
Application of results in practice
5. Evaluating Performance

Auditing evidence-based decisions
Oxford Centre for Evidence-Based Medicine (CEBM) www.cebm.net
Evidence-Based Medicine

Why Evidence-Based Medicine?

clinical decision making is complex!
Mulrow CD, Cook DJ, Davidoff F. Ann Intern Med. 1997;126(5):389-91
Evidence-Based Medicine

How do we practice Evidence-Based Medicine?

It can be difficult!

“information
overload”  difficult for clinicians to “keep up” with all of
the latest evidence

often there are multiple studies examining the same or similar questions
 may be of variable quality, generalizability

estimated time required for reading (general medicine):
 19 articles per day, 365 days per year
Davidoff F et al. BMJ. 1995;310(6987):1085-6
Evidence-Based Medicine

Weighing the evidence - “Levels of Evidence”
OCEBM Levels of Evidence Working Group. “The Oxford 2011 Levels of Evidence”,
Oxford Centre for Evidence-Based Medicine. www.cebm.net/index.aspx?o=5653
Evidence-Based Medicine
of RCTs
Systematic reviews of
cohort studies
Systematic Reviews

What is a Systematic Review?

the application of strategies that limit bias in the assembly,
critical appraisal, and synthesis of all relevant studies on a
specific topic

use rigorous, standardized methods for selecting & assessing articles
Oxford Centre for Evidence-Based Medicine www.cebm.net/?o=1116
OR

a report that summarizes all evidence that can be drawn from
research (or other sources), that is relevant to a specific clinical
question
Systematic Reviews

Systematic Reviews vs. Traditional Review Articles

traditional review articles




written by senior expert in the field, summarizes evidence and
recommendations
usually address broad areas/questions (i.e. “management of T2DM”)
often lack structure
may include personal experience/anecdotal evidence
Fletcher RH & Fletcher SW 2005. Clinical Epidemiology: The Essentials
Systematic Reviews

Systematic Review vs. Traditional/Narrative Review
Cook DJ, Mulrow CD, Haynes RB. Ann Intern Med. 1997;126(5):376-380
Systematic Reviews
Guyatt G et al. 2008. Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2nd Edition)
Systematic Reviews

Process of Conducting a Systematic Review
1. Define the question
2. Conduct literature search
3. Apply inclusion and exclusion criteria
4. Create data abstraction
5. Conduct analysis
Guyatt G et al. 2008. Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2nd Edition)
Systematic Reviews - Process

1. Define the Question

single, focused question


i.e. What is the effectiveness of using a powered (electric) toothbrush
compared with using a manual toothbrush for maintaining oral health?
specify inclusion and exclusion criteria

Population, Intervention or Exposure, Outcome, Methodology

For the systematic review to be useful:


strong studies of the question should be available, but their results should
not be so much in agreement that the question is already answered!
there should not be so few studies of the question that each individual study
could be fully critiqued directly
Systematic Reviews - Process

2. Conduct literature search

need to ensure that all of the appropriate studies are included


decide on information sources


NOT just a biased sample of studies
i.e. MEDLINE, recent reviews, textbooks, experts in the field, articles
cited by references already found by other approaches, databases of
articles, clinical trial registries etc.
identify titles and abstracts
Systematic Reviews - Process

3. Apply inclusion and exclusion criteria

Apply inclusion and exclusion criteria to titles and abstracts


obtain full articles for eligible titles and abstracts
Apply inclusion and exclusion criteria to full articles

Select final eligible articles

Assess agreement on study selection

Of the initial titles and abstracts retrieved, usually only a small
proportion of articles are selected
Systematic Reviews - Process

4. Create data abstraction



Assess methodologic quality of each article
Assess agreement on validity assessment
Data abstraction




Participants
Interventions and Comparison Interventions
Study Design
Results
Systematic Reviews - Process

5. Conduct analysis

Summarize data

If appropriate: meta-analysis – statistical technique to combine
quantitative data


Describe results – often graphically




usually combine studies vs. combine patients
Forest Plot – shows point estimate and confidence interval (for RCTs,
observational studies)
Summary Receiver-Operator Curves (for studies of diagnostic tests)
Explore heterogeneity, conduct subgroup analysis (if appropriate)
Explore possibility of publication bias (and other biases) (i.e. funnel
plot)
Systematic Reviews - Process

How to decide if appropriate to perform a meta-analysis?

Two general approaches:

1. statistical test for homogeneity

BUT – even if fail to reject H0 (i.e. no evidence of a statistically significant
difference between studies), usually have high risk of false-negative (saying
studies are homogeneous when they really are not)


Limited power - meta-analyses are usually of few number of studies,
- affected also by number of patients/study, distribution of patients
among studies
2. informed judgement
Systematic Reviews - Process

Meta-analysis – mathematical models:

Fixed-Effect Model



Assumes that studies are of exactly the same question, so results differ
only by chance
Confidence intervals calculated may imply more precision (i.e. are
narrower) than in reality (since studies usually differ somewhat)
Random-Effects Model



Assumes that the studies address somewhat different questions, but
that they form a closely related family of studies of a similar question
Studies taken to be a random sample of all studies bearing on the
question
Produces WIDER confidence intervals (more “realistic”)
Fletcher RH & Fletcher SW. 2005. Clinical Epidemiology: the Essentials (4 th Edition)
Systematic Reviews – Forest Plot
Impact of Treatment on Mortality
Study name
Kelly, 1964
Hedrin, 1980
Leigh, 1962
Novak, 1992
Saint, 1998
Pilbean, 1936
Day, 1960
Kelly, 1966
Singh, 2000
Stewart, 1994
Statistics for each study
Odds
ratio
Lower
limit
0.590
0.464
0.394
0.490
1.250
0.129
0.313
0.429
0.718
0.143
0.328
0.096
0.201
0.076
0.088
0.479
0.027
0.054
0.070
0.237
0.082
0.233
Odds ratio and 95% CI
Upper
limit
3.634
1.074
2.055
2.737
3.261
0.605
1.805
2.620
2.179
0.250
0.462
0.01
0.1
Favours Tx
Meta Analysis
1
10
Favours Pbo
100
Systematic Reviews - Bias

Several types of bias:

publication bias


language bias


i.e. if only English-language articles are selected
size bias


published studies may be systematically different than unpublished studies
(“positive” studies vs. “negative” studies?)
large studies that result in several publications may be more readily noticed
than smaller studies
bias related to funding?

industry-sponsored studies
How to detect publication bias?

Funnel plots – plot effect vs. study size/precision
symmetrical,
peaked distribution
(inverted funnel)
Guyatt G et al. 2008. Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2nd Edition)
How to detect publication bias?

Funnel plots
asymmetrical
distribution
Guyatt G et al. 2008. Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2nd Edition)
Systematic Reviews - Strengths

provide an efficient way to become familiar with the best
available research evidence for a focused clinical question

can establish whether results are consistent, generalizable
across populations/settings, treatment variations, and whether
findings vary by certain subgroups

can extend the available literature (if the review team has
obtained unpublished information from the primary authors)

meta-analyses – may provide a more precise estimate of the
underlying “true effect” than any individual study
Garg AX, Hackam D, Tonelli M. 2008. Clin J Am Soc Nephrol. 3(1):253-60.
Systematic Reviews - Limitations

summarized results are limited by the quality of the primary
studies


garbage out”
results dependent on selection of included articles


“garbage in
quality threshold, publication bias, language bias etc.
meta-analyses - may be inappropriate to mathematically
combine primary study results if the primary studies differ in
design, quality, population, intervention etc.


subjectivity involved in deciding whether to pool or not
subjectivity in interpretation of summarized results (“overinterpretation)
Garg AX, Hackam D, Tonelli M. 2008. Clin J Am Soc Nephrol. 3(1):253-60.
Systematic Reviews – Critical Appraisal
Oxman AD, Cook DJ, Guyatt GH, Evidence-Based Medicine Working Group. JAMA. 1994;272(17):1367-71
Tonelli M, Hackam D, Garg AX. Methods Mol Biol. 2009;473:217-33
Critical Appraisal – Tools
Oxford Centre for Evidence-Based Medicine http://www.cebm.net/index.aspx?o=1157
Critical Appraisal – Tools
Oxford Centre for Evidence-Based Medicine http://www.cebm.net/index.aspx?o=1157
Critical Appraisal – Tools

AMSTAR – 2007

Assessment of Multiple SysTemAtic Reviews


Shea BJ, Grimshaw JM, Wells GA et al.
11 item tool

developed via exploratory factor analysis of a 37-item assessment
tool
Shea BJ, Grimshaw JM, Wells GA et al. BMC Med Res Methodol. 2007;7:10
Critical Appraisal - Tools
Shea BJ, Grimshaw JM, Wells GA et al. BMC Med Res Methodol. 2007;7:10
Reporting Systematic Reviews - Tools

The PRISMA Statement – 2009

Preferred Reporting Items for Systematic reviews and MetaAnalyses

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group






PLoS Medicine
Annals of Internal Medicine
BMJ
Journal of Clinical Epidemiology
Open Medicine
International Journal of Surgery
The PRISMA Statement - 2009

Aim – to help authors improve the reporting of
systematic reviews and meta-analyses

**NOT intended to be a quality assessment tool


27 item checklist
four-phase flow diagram

update and expansion of prior QUOROM statement

QUality Of Reporting Of Meta-analyses - 1996

focused on reporting of meta-analyses of randomized controlled trials
Table 1. Checklist of items to include when reporting a systematic review or meta-analysis.
Moher D, Liberati A, Tetzlaff J, Altman DG, et al. (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses:
The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed.1000097
Figure 1. Flow of information through the different phases of a systematic review.
Moher D, Liberati A, Tetzlaff J, Altman DG, et al. (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses:
The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed.1000097
Example of a Systematic Review
Cochrane Database of Systematic Reviews 2014 June, Issue 6: CD002281
Powered Toothbrushes for Oral Health

Objective – to compare manual and powered tootbrushes in everyday
use, by people of any age, in relation to the removal of plaque, the health
of the gingivae, staining and calculcus, dependability, adverse effects and
cost

Selection criteria – RCTs of ≥ 4 weeks of unsupervised powered
toothbrushing vs. manual toothbrushing for oral health in children/adults

included:


cross-over trials if wash-out period length was > 2 weeks (to diminish any carry-over
effects)
any type of powered toothbrushes


side to side, counter oscillation, rotation oscillation, circular, ultrasonic, ionic
excluded:


trials only comparing different kinds of powered brushes or different kinds of manual
brushes
“split-mouth” trials – not representative of everyday use
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Powered Toothbrushes for Oral Health

Primary outcomes – quantified levels of plaque, gingivitis, or both



plaque index – Quigley Hein (Turesky), Silness and Löe, Ainamo Bay, Navy plaque
index mod Rustogi, O’Leary index
gingivitis index – Löe Silness, Lobene gingivial index, Bleeding on Probing (BOP),
Papillary bleeding index
where possible, values recorded on arrival at the assessment


If necessary, measures of gingivitis taken after participants permitted to brush teeth at
the assessment visit were used (assumed that toothbrushing would not affect gingivitis
within such a short period)
but, measures of plaque taken after participants brushed teeth at assessment
visit were NOT used
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Powered Toothbrushes for Oral Health

Secondary outcomes - levels of calculus and staining,
dependability and cost of the brush used, adverse effects
(hard/soft tissue injury, damage to orthodontic appliances and
prostheses)

Data classification – short term (1-3 months), long term (>3
months)

If ≥ 4 studies in meta-analysis, random-effects model used
(otherwise fixed-effects model used)
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Risk of Bias Summary

Review authors’ judgements about each
“risk of bias” item for each included study
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Risk of Bias Graph

Review authors’ judgements about each “risk of bias” item presented as
percentages across all included studies
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Results – Powered vs. Manual Brushes

Primary
outcome –
plaque
scores at >
3 months
Results – Powered vs. Manual Brushes

Primary
outcome –
gingival
scores at >
3 months
Results – Powered vs. Manual Brushes

Primary
outcome –
gingival
scores at >
3 months
Assessment of Publication Bias
Assessment of Publication Bias
Results

Secondary outcomes:
 Cost – none of the trials reported on relative costs
 Reliability – 2 trials


Calculus – 3 trials


2 trials – no significant difference; 1 trial – powered brush better
Stain – 3 trials


mechanical failure in 1/48 and 4/20 powered toothbrushes
no significant difference between brush types
Adverse events – tissue trauma – 40 trials

27 trials – no trauma; 6 trials – no difference between brush types; 7 trials
– differences between brush types
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Discussion

Moderate quality evidence exists that demonstrate that powered
toothbrushes provide a statistically significant benefit compared
with manual toothbrushes for both reduction of plaque and
gingivitis



plaque: as per Quigley Hein index - 11% reduction short term, 21%
reduction long term
gingivitis: as per Löe Silness index – 6% reduction short term, 11% reduction
long term
However, high levels of heterogeneity that was not explained by
the different powered toothbrush type subgroups
 Greatest body of evidence – for rotation oscillation brushes

(statistically significant reduction in plaque and gingivitis at both
time points)
Conclusions

Powered toothbrushes reduce plaque and gingivitis more than
manual toothbrushes in the short and long term
 clinical importance of findings remain unclear

Greater standardization of design of future studies/meta-analyses
would be beneficial

Cost, reliability and side effects were not consistently reported
 any reported side effects were localized and only temporary
Systematic Reviews – Critical Appraisal
Oxman AD, Cook DJ, Guyatt GH, Evidence-Based Medicine Working Group. JAMA. 1994;272(17):1367-71
Tonelli M, Hackam D, Garg AX. Methods Mol Biol. 2009;473:217-33
Useful Resources

Guyatt G, Rennie D, Meade MO, Cook DJ. 2008. Users’ Guide to
the Medical Literature: A Manual for Evidence-Based Clinical
Practice (2nd Edition). New York NY, McGraw-Hill


Oxford Centre for Evidence-Based Medicine (CEBM)


available online via Western Libraries
www.cebm.net
Cochrane Database of Systematic Reviews

www.thecochranelibrary.com
References

Sackett DL, Rosenberg WMC, Muir Gray JA, Haynes RB, Richardson WS. BMJ. 1996;312(7023):71-2

Mulrow CD, Cook DJ, Davidoff F. Ann Intern Med. 1997;126(5):389-91

Davidoff F, Haynes B, Sackett D, Smith R. BMJ. 1995;310(6987):1085-6

Oxford Centre for Evidence-Based Medicine (CEBM) www.cebm.net

OCEBM Levels of Evidence Working Group. “The Oxford 2011 Levels of Evidence”, Oxford
Centre for Evidence-Based Medicine. www.cebm.net/index.aspx?o=5653

Fletcher RH & Fletcher SW. 2005. Clinical Epidemiology: the Essentials (4th Edition). Baltimore MD,
Lippincott Williams & Wilkins

Guyatt G, Rennie D, Meade MO, Cook DJ. 2008. Users’ Guide to the Medical Literature: A Manual
for Evidence-Based Clinical Practice (2nd Edition). New York NY, McGraw-Hill

Cook DJ, Mulrow CD, Haynes RB. Ann Intern Med. 1997;126(5):376-380

Garg AX, Hackam D, Tonelli M. 2008. Clin J Am Soc Nephrol. 3(1):253-60.

Oxman AD, Cook DJ, Guyatt GH, Evidence-Based Medicine Working Group. JAMA.
1994;272(17):1367-71

Tonelli M, Hackam D, Garg AX. Methods Mol Biol. 2009;473:217-33

Cochrane Database of Systematic Reviews www.thecochranelibrary.com