Medical Literature: Reading, Interpreting, and Writing Muhammad Mamdani, PharmD, MA, MPH Director, Applied Health Research Centre LKSKI of St. Michael’s Hospital Associate Professor – University of Toronto Adjunct Faculty – King Saud University February 2010
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Medical Literature:
Reading, Interpreting, and Writing
Muhammad Mamdani, PharmD, MA, MPHDirector, Applied Health Research Centre
LKSKI of St. Michael’s HospitalAssociate Professor – University of Toronto
Adjunct Faculty – King Saud UniversityFebruary 2010
Objectives
To better understand the basic purpose of research and the context under which research is conducted
To review basic clinical research study designs
To review two standard study review tools
To review basic principles in writing clinical research manuscripts
Clinical Research: Basic Purpose and Context
The Common Goal of Research
‘The’ GoalAttempt to estimate the ‘truth’
TRUTH
Study 3Study 1 Study 2
Perception: Reality vs Belief
Variability in Perceptions
The Trouble with ResearchExample: H. pylori eradication and non-ulcer dyspepsia
McColl et al (NEJM, 1998)Treatment (n=154): Omeprazole 20 mg bid + amoxicillin 500 mg tid + 400 mg metronidazole tid x 2 weeks
Comparison (n=154): omeprazole 20 mg bid x 2 weeksSymptom resolution at 1 year: Tx = 21% vs. Comparison = 7% (p<0.001)
Blum et al (NEJM, 1998)Treatment (n=164): Omeprazole 20 mg bid + amoxicillin 1000 mg bid + 500 mg clarithromycin bid x 1 week
Comparison (n=164): omeprazole 20 mg bid x 1 weekSymptom resolution at 1 year: Tx = 27% vs. Comparison = 21% (p=0.17)
The Evolving Nature of Research
The Evolving Nature of Research
Analyzed 115 articles published in 1990-2003 in the 3 major general medical journals (NEJM, JAMA, Lancet) and specialty journals that had received over 1000 citations each by August 2004
49 reported evaluations of health care interventions; 45 claimed that the interventions were effective.
By 2004 5/6 non randomised studies and 9/39 randomised trials were already contradicted or found to be exaggerated
Ioannidis JP. JAMA 2005
But How Do I Know About the Quality and Validity
of the Study?
Understanding Clinical Research: What do I Need to Fully Interpret a
Clinical Study?
Understand Clinical Research Methodology: Epidemiology
Observational Research STROBE Statement http://www.strobe-statement.org/
Consort Statement
STROBE
Group Activity: Pitt et al
Group Exercise20 Minutes Group Review
One person from each group to present for up to 2 minutes
Use CONSORT
GroupsGroup 1: Abstract and IntroductionGroup 2: MethodsGroup 3: ResultsGroup 4: Comment – make recommendation
Pitt et al: Study Overview
RALES: Randomized ALdactonE StudyPitt et al, N Engl J Med, 1999
Double-blind randomized controlled trial in patients with congestive heart failure
Primary endpoint: all-cause mortality
Screened (n=?)
Randomize
Spironolactone (n=822)
25 mg po qd
- Increase to 50 mg po qd where tolerated
Placebo (n=841)
Inclusion Exclusion
RALES Criteria
Inclusion / ExclusionNYHA class III or IV at time of enrolmentLVEF < 35% within 6 monthsExclude patients with serum creatinine 2.5 mg/dL or serum potassium > 5 mmol/L
Follow-upLab and clinic follow-up at 4 weeks and 3 and 6 months
Appropriate use of ACE inhibitors and beta-blockers
D/c K-sparing diuretics and K+ supplementsHolding spironolactone for hyperkalemia or creatinine > 4 mg/dL
In the ‘Real World’….Different patients may get the drug
> 50% of population that would normally use the drugs in clinical practice often do not meet inclusion / exclusion criteria of RCTs (e.g. Gill et al, CJCP, 2004)
Patients may not be monitored as carefully
Patients may not take their drug as they should
Patients may take interacting drugs that they shouldn’t be on
% Patients with LVEF < % Patients with LVEF < 35%35%
54.8%54.8% 100%100%
% Patients with renal % Patients with renal insufficiency at insufficiency at baselinebaseline
30.7%30.7% ExcludedExcluded
Use of beta-blockersUse of beta-blockers 34.6%34.6% 11%11%
In a highly selected group of patients with severe heart failure who are largely free of other risk factors for hyperkalemia and who can be monitored closely, the addition of spironolactone to standard therapy (as defined in 1994) decreases hospitalization for heart failure and saves lives, with no significant risk of hyperkalemia.
What RALES said…
What we heard…• In patients with heart failure, spironolactone saves lives
Interpreting Evidence: Key Points
Interpretation of evidence depends on:
Availability of evidence
Ability to understand, assimilate, and interpret evidence and its limitations
Putting It All Together
What Drives Interpretation?
Study design / methodologyAppropriate design Inclusiveness / generalizability
Statistical analysis and reporting
Clinical relevance and ‘sense’
Where Does Evidence Fit Into the Decision-Making Process?
BELIEFS
BEHAVIOUR
Evidence Personal Values / Experience
Societal Values ‘Other’ Factors
Clinical Research:Writing a Scientific
Manuscript
What Do Journal Editors Look For?
Characteristic Implications
Clinical Relevance
Research question should be relevant:Ask other clinicians about question’s clinical importance
Originality Research question should ideally be unique:Perform a PubMed search
Clarity Research question should be simpleStudy design should be well explained with ONE primary endpointBefore beginning study – know which 4 or 5 figures and/or tables will be produced; make mock figures/tablesKnow your audience: simple language
Good Science Assemble a team: study lead, methodologist, statistician, clinician, at least one senior researcherMust have good design, sufficient sample size, and analysis plan
Brevity Keep the manuscript short: 2,000 – 3,000 wordsConsider different formats: brief reports, research letters
What will maximize the journal’s IMPACT FACTOR?
Fogg, BJ, et al, What makes Websites Credible? Stanford Persuasive Technology Lab
Author Photo Results
believable
trustworthy
competent
credible
unbiased
expert
COMPOSITE
casual photo
no photo
formal photo
Fogg, BJ, et al, What makes Websites Credible? Stanford Persuasive Technology Lab
The Anatomy of a Clinical Research Question
Is the question simple?The question must be easy to understand and the results must be easy to convey
Start with thinking about the 4 or 5 Tables or Figures that would result from your research
Is the question important?It should be important to others besides the researcher
Is it the question unique?Must have a solid background / contextExtensive literature search to assess novelty of the research
Is the question specific?ExposureOutcome: reflects only ONE well-defined primary endpoint
Nature of assessment (e.g. relationship vs. difference – need to state intervention)
Research ImpactHigh Impact
Great questions Great questionsGreat findings Poor findings
Low Impact
Poor questions
Great findings
No ImpactNo Impact
Poor questions Poor questions
Poor findingsPoor findings
Other ConsiderationsBefore beginning your study, know which journal(s) you would like to targetCarefully review their format requirements (usually on website)
Review sample studies from that journal
Focus on a good abstractMany journals screen articles for review based on the abstract
Review past article’s abstracts for format and wording style
Make cover letter brief but relevantProvide clinical context and rationale for the studyBriefly summarize study findingsBriefly summarize implications of study findings on clinical practice and/or public health
Try to keep it brief – maximum 1 page
Research and Communications: An Example
BackgroundA particular group of antibiotics called ‘fluoroquinolone’ antibiotics have become the most widely prescribed group of antibiotics About 22 million prescriptions dispensed annually in US for fluoroquinolone
antibiotics 16 individual fluoroquinolone antibiotics have been available on the
market; In 2005, gatifloxacin (Tequin) was the fluoroquinolone antibiotic of choice for US public health system
Some of these drugs have problems: serious adverse events have led to the withdrawal or restriction of several fluoroquinolones in recent years Temafloxacin (blood sugar and kidney problems) Grepafloxacin and sparfloxacin (heart problems) Trovafloxacin (liver problems)
In 2005, a student noticed major changes in blood glucose levels in patients receiving Tequin and approached researchers to investigate this observation
So We Conducted a Study (Park-Wyllie et al, NEJM, 2006)
PopulationExamined records of over 1.4 million elderly residents of Ontario age 66 years and older between 2002-2004
Analysis limited to individuals who were using one of several selected antibiotics
OutcomesHospital admission related to severe changes in blood glucose levels
What Were the Results?
Hospital admissions related to severe drops in blood glucose levelsGatifloxacin associated with 4x the risk of hospital admission compared to other antibiotics
Hospital admissions related to severe increases in blood glucose levelsGatifloxacin associated with almost 17x the risk of hospital admission compared to other antibiotics
The Basic Communications Plan
Raise the profile of the issue
Make the numbers tangible and meaningful
Target the right journal
Identify the appropriate audiences
Making the Numbers Tangible
If we consider the 1.4 million elderly residents of Ontario during the study timeframe:
There were nearly 17,000 courses of gatifloxacin treatment administered
For every 100 courses of gatifloxacin, we may expect 1 hospital admission for dysglycemia
On average, it was estimated that at least 1 elderly person in Ontario was hospitalized every week as a result of dysglycemia that was likely associated with gatifloxacin
ImpactPublished early online (March 1st, 2006) in the New England Journal of Medicine given its clinical relevance
Recognized nationally as a significant research contribution:Canadian Society of Clinical Pharmacology