1. Clinical Epidemiology Boot Camp: Systematic Reviews Selina Liu MD MSc FRCPC Cert Endo December 17, 2014

2. 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

3. 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-19 th century Paris (or possibly earlier) Sackett DL et al. BMJ. 1996;312(7023):71-2

4. 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.netwww.cebm.net

5. 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

6. 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

7. 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=5653www.cebm.net/index.aspx?o=5653

8. Evidence-Based Medicine Systematic reviews of cohort studies of RCTs

9. 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=1116www.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

10. 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

11. Systematic Reviews  Systematic Review vs. Traditional/Narrative Review Cook DJ, Mulrow CD, Haynes RB. Ann Intern Med. 1997;126(5):376-380

12. Systematic Reviews Guyatt G et al. 2008. Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2 nd Edition)

13. 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 (2 nd Edition)

14. 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

15. 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

16. 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

17. 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

18. 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)

19. 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 H 0 (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

20. 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)

21. Systematic Reviews – Forest Plot

22. 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

23. 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 (2 nd Edition)

24. 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 (2 nd Edition)

25. 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.

26. 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.

27. 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

28. Oxford Centre for Evidence-Based Medicine http://www.cebm.net/index.aspx?o=1157http://www.cebm.net/index.aspx?o=1157 Critical Appraisal – Tools

29. Oxford Centre for Evidence-Based Medicine http://www.cebm.net/index.aspx?o=1157http://www.cebm.net/index.aspx?o=1157

30. 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

31. Critical Appraisal - Tools Shea BJ, Grimshaw JM, Wells GA et al. BMC Med Res Methodol. 2007;7:10

32. 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

33. 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

34. 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

35. 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

36. Example of a Systematic Review Cochrane Database of Systematic Reviews 2014 June, Issue 6: CD002281

37. 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

38. 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

39. 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

41.  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

42.  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

43.  Primary outcome – plaque scores at > 3 months Results – Powered vs. Manual Brushes

44.  Primary outcome – gingival scores at > 3 months Results – Powered vs. Manual Brushes

45.  Primary outcome – gingival scores at > 3 months Results – Powered vs. Manual Brushes

46. Assessment of Publication Bias

48.  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

49.  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)

50.  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

51. 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

52. Useful Resources  Guyatt G, Rennie D, Meade MO, Cook DJ. 2008. Users’ Guide to the Medical Literature: A Manual for Evidence-Based Clinical Practice (2 nd Edition). New York NY, McGraw-Hill  available online via Western Libraries  Oxford Centre for Evidence-Based Medicine (CEBM)  www.cebm.net www.cebm.net  Cochrane Database of Systematic Reviews  www.thecochranelibrary.com www.thecochranelibrary.com

53. 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.netwww.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=5653www.cebm.net/index.aspx?o=5653  Fletcher RH & Fletcher SW. 2005. Clinical Epidemiology: the Essentials (4 th 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 (2 nd 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.comwww.thecochranelibrary.com