clinical epidemiology boot camp: systematic reviews selina liu md msc frcpc cert endo december 17,...
TRANSCRIPT
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 Translation of uncertainty to an answerable question
2. Finding the Evidence Systematic retrieval of the best evidence available
3. Critical Appraisal Testing evidence for validity, clinical relevance, and applicability
4. Making a Decision 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
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 articlesOxford 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 search3. Apply inclusion and exclusion criteria4. Create data abstraction5. 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 NOT just a biased sample of studies
decide on information sources 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 usually combine studies vs. combine patients
Describe results – often graphically 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 (4th Edition)
Systematic Reviews – Forest Plot
Study name Statistics for each study Odds ratio and 95% CI
Odds Lower Upper ratio limit limit
Kelly, 1964 0.590 0.096 3.634Hedrin, 1980 0.464 0.201 1.074Leigh, 1962 0.394 0.076 2.055Novak, 1992 0.490 0.088 2.737Saint, 1998 1.250 0.479 3.261Pilbean, 1936 0.129 0.027 0.605Day, 1960 0.313 0.054 1.805Kelly, 1966 0.429 0.070 2.620Singh, 2000 0.718 0.237 2.179Stewart, 1994 0.143 0.082 0.250
0.328 0.233 0.462
0.01 0.1 1 10 100
Favours Tx Favours Pbo
Impact of Treatment on Mortality
Meta Analysis
Systematic Reviews - Bias
Several types of bias:
publication bias published studies may be systematically different than
unpublished studies (“positive” studies vs. “negative” studies?)
language bias i.e. if only English-language articles are selected
size bias 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
asymmetricaldistribution
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 in garbage out”
results dependent on selection of included articles 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
(“over-interpretation)Garg AX, Hackam D, Tonelli M. 2008. Clin J Am Soc Nephrol. 3(1):253-60.
Systematic Reviews – Critical Appraisal
Tonelli M, Hackam D, Garg AX. Methods Mol Biol. 2009;473:217-33
Oxman AD, Cook DJ, Guyatt GH, Evidence-Based Medicine Working Group. JAMA. 1994;272(17):1367-71
Oxford Centre for Evidence-Based Medicine http://www.cebm.net/index.aspx?o=1157
Critical Appraisal – Tools
Critical Appraisal – Tools
Oxford Centre for Evidence-Based Medicine http://www.cebm.net/index.aspx?o=1157
Critical Appraisal – Tools
Shea BJ, Grimshaw JM, Wells GA et al. BMC Med Res Methodol. 2007;7:10
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
Reporting Systematic Reviews - Tools
The PRISMA Statement – 2009 Preferred Reporting Items for Systematic reviews and
Meta-Analyses
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
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 useYaacob 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
Review authors’ judgements about each “risk of bias” item for each included study
Risk of Bias Summary
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Review authors’ judgements about each “risk of bias” item presented as percentages across all included studies
Risk of Bias Graph
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
Secondary outcomes: Cost – none of the trials reported on relative costs Reliability – 2 trials
mechanical failure in 1/48 and 4/20 powered toothbrushes Calculus – 3 trials
2 trials – no significant difference; 1 trial – powered brush better
Stain – 3 trials 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
Results
Yaacob M. et al. Cochrane Database of Syst Rev 2014, Issue 6:CD002281
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
Discussion
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)
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
Conclusions
Systematic Reviews – Critical Appraisal
Tonelli M, Hackam D, Garg AX. Methods Mol Biol. 2009;473:217-33
Oxman AD, Cook DJ, Guyatt GH, Evidence-Based Medicine Working Group. JAMA. 1994;272(17):1367-71
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 available online via Western Libraries
Oxford Centre for Evidence-Based Medicine (CEBM) 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