Reading and Analyzing Scientific Articles. Wednesday, October 20, 2010

Transcription

1 Reading and Analyzing Scientific Articles Wednesday, October 20, 2010

2 Zuber D. Mulla, Ph.D. Associate Professor & Director of Epidemiologic Research Department of OB/GYN and Affiliate Associate Professor Dept. of Epidemiology & Biostatistics University of South Florida College of Public Health Tampa, Florida (915)

3 Overview Highlight aspects of evaluating the literature Review incidence, biology, and medical management of invasive group A streptococcal disease Critique randomized controlled trial by Darenberg et al.

4 Objectives Define what is an experiment and what is an observational study List the 3 alternative explanations, other than truth, of an observed association (or lack of association) Name a website that performs simple statistical calculations

5 Case Report 1 17 year-old male No HIV infection No DM Hird & Byrne, J Trauma 1994

6 Case Report 1 Next 3 days: vomiting, fever, swelling and pain 4 days after sx onset: admitted

7 Case Report 1 Pulse of 155 Blood pressure: 90/65 Confused CK 33,000 u/l AST 233 ALT 63

8 Review elements Background: Can the research question survive the, So what? test? Unique? Methods: Inclusion & exclusion criteria Sample size calculation For trials: analysis with intention to treat? Appropriate data analysis? Nesting/clustering accounted for? Results Conclusion: Balanced? Causality criteria.

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10 What is an experiment? What is a clinical trial? What is an observational study?

11 Alternative Explanations Truth

12 References Current literature? Abstracts Letters

13 Introduction Group A Streptococcus (GAS) or Streptococcus pyogenes Very important human pathogen Impetigo, scarlet fever, puerperal fever, pharyngitis, erysipelas

14 Introduction Streptococcal toxic-shock syndrome (very high CFR) Necrotizing fasciitis Septicemia Septic arthritis

15 Descriptive Epidemiology >10 million noninvasive infections a year in the U.S. 10,000 cases of invasive GAS disease (U.S. annual incidence = 3.7 per 100,000) 4 to 6 times that of meningococcal disease

16 Antibiotic of choice?

17 Treatment Penicillin, Debridement for NF However, mice models have shown penicillin fails when large number of streptococci are present Eagle Effect

18 Clindamycin vs. Penicillin Clindamycin in mice models protects against mortality even if tx is delayed Suppresses toxin production Inhibits M-protein synthesis

19 Clindamycin All pts in trial by Darenberg and colleagues received clindamycin Any RCTs of clinda s efficacy?

20 Evidence for Clindamycin in Deep GAS Infections First Author Year Type of Study Stevens DL 1988 Animal Zimbelman J 1999 Epidemiologic Mulla Z 2003 Epidemiologic

21 Clindamycin All pts received clinda No RCTs of clinda s efficacy Necrotizing fasciitis and/or streptococcal toxic shock syndrome caused by group A streptococci should be treated with clindamycin and penicillin (A-II). IDSA, CID Nov 2005

22 Evidence for clindamycin A: Good evidence to support a recommendation for use; should always be offered II: Evidence from 1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from 11 center); from multiple time series; or from dramatic results from uncontrolled experiments

23 IVIG: Observational Study Kaul et al. cohort study, Canada, 1999 Significant improvement in survival among cases treated with IVIG Confounded by clinda use?

24 Proposed Biological Plausibility anti-m Abs anti-exotoxin Abs anti-cytokine Abs Norrby-Teglund A et al., Scand JID, 2003

25 Minimal surgical intervention Norrby-Teglund et al., Scand JID, pts with severe soft tissue infection caused by GAS 6 of 7 has streptococcal TSS

26 Minimal surgical intervention Surgery not performed or was only limited exploration High-dose IVIG: 2 g/kg body weight infused over 3 h

27 Minimal surgical intervention All survived Aggressive medical regimen with IVIG, may allow initial nonoperative or minimally invasive approach,

28 Points of Discussion Darenberg et al. Table 1 No p-values Imbalances?

29 Table 1 Definitive STSS Coagulopathy Cytokines

30 2 x 2 Table Verify basic results Table 3 Enter data in or SAS, etc.

31 Verify results What is the RR quoted in abstract? See Results, page 338 (RR and p-value)

32 Null Hypothesis Usually the hypothesis of no difference H o : RR = 1 H A : RR 1 Two-tailed test

33 One-tailed vs. Two-tailed Test Which is appropriate? Sample size

34 Broad topic Sample Size Type of analysis dictates sample size calculation Size depends on multiple factors including: Power Type I error What difference do you want to detect?

35 Sample Size Will randomize patients to 1 of 2 treatments 70% vs. 10%?

36 Sample Size Will randomize patients to 1 of 2 treatments 70% vs. 60%?

37 Take Home Message on Sample Size 70% vs. 10%: smaller N than 36% vs. 10% Large difference: smaller N Consult biostatistician or epidemiologist

38 Tests Used Fisher s exact Mann-Whitney U (Wilcoxon rank sum for 2 independent samples)

39 Opinions of Stevens D The current study was well-designed, well executed The results are encouraging However it is doubtful that, on the basis of existing evidence, the US Food and Drug Administration would officially sanction the use of IVIG to treat Strep TSS.

40 Opinions of Stevens D Yet we may never have the luxury of gathering data from a larger study Thus, if one is pressed to decide whether the use of IVIG constitutes the standard of care for infectious disease physicians, we are on shaky ground.

41 Ask for help Someone with training in epidemiology and biostatistics Faculty with experience in publishing and the peer-review process

42 References Epidemiology in Medicine, by Charles Hennekens, MD, DrPH, and Julie Buring, ScD Little, Brown, and Co. (1987) Clinical Trials: A Practical Approach, by Stuart Pocock John Wiley & Sons (1983)

43 References Epidemiology: An Introduction, by Kenneth Rothman Oxford University Press (2002) Dilemmas in the Treatment of Invasive Streptococcus pyogenes Infections, by Denny Stevens, PhD, MD, Clinical Infectious Diseases, August 1, 2003, p. 341