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Clinical Writing for
Interventional
Cardiologists
What you will learn
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Introduction
General principles for clinical writing
Specific techniques
Practical session: critical review of a published article
Writing the Title and the Abstract
Bibliographic search and writing the Introduction
Principles of statistics and writing the Methods
Practical session: writing the Abstract
Writing the Results
Writing the Discussion
Writing Tables and preparing Figures
Principles of peer-review
Principles of grant writing/regulatory submission
Clinical writing at a glance
Conclusions and take home messages
Materials and methods
How was the problem studied?
The answer is in the Methods
Materials and methods
The Methods section is often the
less read section, but it is the
most important because allow us
to understand how the study
was conducted, thus giving us
an idea of the value of its results
Expanded IMRAD algorithm
Introduction
Background
Limitations of current evidence
Study hypothesis
Methods
Design
Patients
Procedures
Follow-up
End-points
Additional analyses
Statistical analysis
Results
Baseline and procedural data
Early outcomes
Mid-to-long term outcomes
Additional analyses
Discussion
Summary of study findings
Current research context
Implications of the present study
Avenues for further research
Limitations of the present study
Conclusions
Materials and methods
• Describe with full details what was done to
answer the research question
• In the beginning include a clear statement of
study design:
“The study was a double-blind, randomized, parallel
design … designed to compare the efficacy and safety
of …”
• Include also a sentence about IRB approval,
informed consent, or compliance with animal
welfare regulations:
“The protocol was approved by the institutional review
board, and all patients gave informed consent …”
Materials and methods
RRISC JACC 2006
Materials and methods
• State the protocol/procedures. Repeat the
question and the aims:
“We tested the efficacy of drug XX administered orally
in a dose of XX mg, given XX times daily for up to XX
months.”
“There were 2 primary endpoints. The first was eventfree survival at XX days, with an event defined as…”
• Describe materials/methods or subjects
adequately
• Write in a logical order (usually chronological)
• Describe analytical methods
Materials and methods
• Use subheadings (design, patients,
procedures, follow-up, endpoints….)
• Do not include results in Methods
• Include appropriate figures and tables if
useful to graphically explain concepts
• Write in past tense
• Use active voice whenever possible
• Cite references for published methods
• Describe new methods fully
Materials and methods
• Briefly address questions you can anticipate
from the reader, e.g. justify/clarify the design
of your study:
“Intra-luminal recanalization of long coronary artery
occlusions cannot be obtained in all patients. …. We
thus tested the feasibility and safety of subintimal
angioplasty in patients in whom standard intraluminal approaches had failed and who were not
candidate to bypass surgery because of severe
comorbidities…”
Materials and methods
If you prevent major limitations in your study, treat
them in a matter-of-fact way:
"This study was performed as part of a routine
clinical assessment, so that no attempt was made
to ensure either fasting of the patient or
performance of the test at a particular time of day."
What you will learn
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Principles of statistics and writing the
Methods
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study designs
intention-to-treat vs per-protocol analysis
type I and type II errors
p values and confidence intervals
Design subsection
• State clearly the design of the study
• Was it retrospective or prospective?
• Was it a registry or controlled study?
• Did you randomly allocated patients?
• Did you follow a protocol (may add figure)?
You can also include here
details of IRB approval
Prospective non-RCT study
RESOLUTE EuroIntervention 2007
Prospective non-RCT study
Cavallini et al. EHJ 2005
Retrospective non-RCT study
Biondi-Zoccai et al. EHJ 2006
Prospective RCT study
Tapas NEJM 2008
TAPAS 1 year
Lancet 2008
Prospective RCT study
• State clearly:
• If the trial was double-blind / single-blind /
open-label
• If blinded, how blinding was granted
• how randomization was performed
ENDEAVOR II Circulation 2006
Prospective RCT study
RRISC JACC 2006
Patient subsection
• State clearly how you selected
patients
• Specific inclusion criteria?
• Specific exclusion criteria?
You can include here details
of written informed consent
Tapas NEJM 2008
Patient subsection
Procedure subsection
• State clearly how you performed the procedure
• Any novel approaches or devices?
• Complete with details on concomitant or postintervention medications
• If evaluating bio-markers, state clearly which
ones, which essay is used and how it works
You can include here pictures
detailing what you did/use
Procedure subsection
TAPAS NEJM 2008
Procedure subsection
Lefevre et al. CCI 2000
Procedure subsection
Lefevre et al. CCI 2000
Outcome subsection
• State clearly outcomes and who adjudicated them
(independent CEC?)
• Define each outcome thoroughly (death, MI, RR,
TVF, TVR, TLR, ST, bleedings…)
• Define the timing of follow-up and specify info on
follow-up means (how patients were contacted?)
• Make sure you use validated or consensus
definitions / classifications (if available, otherwise
you are in trouble!)
Outcome subsection
ENDEAVOR II
Circulation 2006
Outcome subsection
Spaulding et al.
NEJM 2007
Additional analysis subsection
• Focus on additional analyses that may be
pertinent to the study
– QCA: late loss, binary restenosis…
– TIMI score, Myocardial Blush Grade
– IVUS: neointimal hyperplasia volume, minimal lumen area…
– CT: coronary stenosis > 50%...
– MRI: myocardial infarction mass…
– Echocardiography: LV ejection fraction…
• Quote thoroughly for established methods
• Define explicitly terms and ways to compute
secondary variables
Additional analysis subsection
TAPAS NEJM 2008
What you will learn
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Principles of statistics and writing the
Methods
–
–
–
–
study designs
intention-to-treat vs per-protocol analysis
type I and type II errors
p values and confidence intervals
Statistics subsection
• Explain how you handled and reported categorical
and continuous variables
• Explain how you tested for significance at both
univariate and multivariate analysis
• Define tails and threshold p value
• State width of confidence intervals
• Provide sample size computation
• Spell out which software package was used
Quote extensively and be ready to defend
yourself if you use sophisticated analytic tools
Types of variables
Variables
CATEGORY
nominal
QUANTITY
ordinal
discrete
continuous
ranks
counting
measuring
TIMI
flow
Stent diameter
Stent length
BMI
Blood pressure
QCA data (MLD, late loss)
Death: yes/no
TLR: yes/no
ordered
categories
Radial/brachial/femoral
Categorical variables
• Categorical variables are probably the most
important ones provided by a clinical study, as
hard clinical end-points are always expressed so
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Specifically, focus on:
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Choose few statistics, and use them consistently
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Provide confidence intervals (usually 95%)
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May also provide number needed to treat/harm
Compare event rates
No TVF
TVF
Driver
a
b
Endeavor
c
d
Absolute Risk = [ d / ( c + d ) ]
Absolute Risk Reduction = [ d / ( c + d ) ] - [ b / ( a + b ) ]
Relative Risk = [ d / ( c + d ) ] / [ a / ( a + b ) ]
Relative Risk Reduction = 1 - RR
Odds Ratio = (d/c)/(b/a) = ( a * d ) / ( b * c )
Compare event rates
Absolute Risk (AR)
7.9% (47/592) & 15.1% (89/591)
Absolute Risk Reduction (ARR)
7.9% (47/592) – 15.1% (89/591) = -7.2%
STENT * TVF Crosstabulation
Count
TVF
STENT
Total
Driver
Endeavor
no
502
545
1047
yes
89
47
136
Total
591
592
1183
Relative Risk (RR)
7.9% (47/592) / 15.1% (89/591) = 0.52
(given an equivalence value of 1)
Relative Risk Reduction (RRR)
1 – 0.52 = 0.48 or 48%
Odds Ratio (OR)
8.6% (47/545) / 17.7% (89/502) = 0.49
(given an equivalence value of 1)
Odds Ratio Reduction (ORR)
1 – 0.49 = 0.51 or 51%
Continuous variables
• Continuous variables are important for the
appraisal of baseline/procedural characteristics
(eg stent length per lesion), or additional
analyses (eg QCA)
• Focus on these points:
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Provide mean and standard deviation
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Or median (interquartile range) if non-Gaussian
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May check for normality assumptions
Mean (arithmetic)
Characteristics:
-summarises information well
-discards a lot of information
(dispersion??)
Cardiology
x
x
N
Assumptions:
-data are not skewed
– distorts the mean
– outliers make the mean very different
-Measured on measurement scale
– cannot find mean of a categorical measure
‘average’ stent diameter may be meaningless
Median
Cardiology
What is it?
– The one in the middle
– Place values in order
– Median is central
Definition:
– Equally distant from all other values
Used for:
– Ordinal data
– Skewed data / outliers
Comparing Measures of central tendency
Cardiology
Mean is usually best
– If it works
– Useful properties (with standard deviation [SD])
– But…
Lesion length
Mean
Median
Driver
Endeavor
17
19
19
17
18
21
21
21
21
6
18
18
18
21
Comparing Measures of central tendency
Cardiology
It also depends on the underlying distribution…
mean = median = mode
Frequency
Symmetric?
Value
Comparing Measures of central tendency
Cardiology
It also depends on the underlying distribution…
mean ≠ median ≠ mode
Asymmetric?
30
Mode
Median
Mean
Frequency
25
20
15
10
5
0
0
1
2
3
4
5
6
7
8
Number of Endeavor implanted per patient
9
Measures of dispersion: examples
Frequency
Cardiology
0
0.30
0.60
0.90
Late loss
Endeavor
Driver
1.20
1.50
Measures of dispersion: examples
Frequency
Cardiology
0
0.30
0.60
0.90
Late loss
Endeavor
Driver
1.20
1.50
Measures of dispersion: examples
Frequency
Cardiology
0
0.30
0.60
0.90
Late loss
Endeavor
Driver
1.20
1.50
Measures of dispersion: types
Cardiology
• Standard deviation (SD)
– Used with mean
– Parametric tests
• Interquartile range
– Used with median
– 25% (1/4) to 75% (3/4) percentile
– Non-parametric tests
• Range
– First to last value
– Not commonly used
Standard deviation
Cardiology
Standard deviation (SD):
– approximates population σ
SD

as N increases
Advantages:
– with mean enables powerful synthesis
mean±1*SD 68% of data
mean±2*SD 95% of data (1.96)
mean±3*SD 99% of data (2.86)
Disadvantages:
– is based on normal assumptions
2
( x x )
N-1
Testing normality assumptions
Cardiology
Rules of thumb
1. Refer to previous data or analyses
(eg landmark articles, large databases)
2. Inspect tables and graphs (eg outliers, histograms)
3. Check rough equality of mean, median,
mode
4. Perform ad hoc statistical tests
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Levene’s test for equality of means
Kolmogodorov-Smirnov tests
…
Inferential statistics
P values tell you whether there is a
DIFFERENCE and its DIRECTION
Confidence intervals tell you what is
the MAGNITUDE (or SIZE) of such difference
Difference and direction
2.1 vs 2.4%
0.3 vs 2.8%
Size of the difference
7.2 vs 2.4%
Sample size calculation
Whenever designing
a study or analyzing
a dataset, it is
important to
estimate the sample
size or the power of
the comparison
To compute the sample size for a study we need:
1. Preferred alpha value
2. Preferred beta value (remember: power is (1-beta)x100)
3. Control event rate or average value
(with measure of dispersion if appliable)
4. Expected relative reduction in experimental group
ENDEAVOR II Circulation 2006
Intention-to-treat analysis
• Intention-to-treat (ITT) analysis is an
analysis based on the initial treatment
intent, irrespectively of the treatment
eventually administered
• ITT analysis is intended to avoid various types of
bias that can arise in intervention research,
especially procedural, compliance and survivor
bias
• However, ITT dilutes the power to achieve
statistically and clinically significant differences,
especially as drop-in and drop-out rates rise
Per-protocol analysis
• In contrast to the ITT analysis, the per-protocol
(PP) analysis includes only those patients who
complete the entire clinical trial or other particular
procedure(s), or have complete data
• In PP analysis each patient is categorized
according to the actual treatment received, and not
according to the originally intended treatment
assignment
• PP analysis is largely prone to bias, and is useful
almost only in equivalence or non-inferiority
studies
ITT vs PP
100 pts
enrolled
50 pts to group A
(more toxic)
45 pts treated with A, 5
shifted to B because of poor
global health (all 5 died)
RANDOMIZATION
ACTUAL THERAPY
50 pts to group B
(conventional Rx, less toxic)
50 patients treated
with B (none died)
• ITT: 10% mortality in group A vs 0% in
group B, p=0.021 in favor of B
• PP: 0% (0/45) mortality in group A vs 9.1%
(5/55) in group B, p=0.038 in favor of A
Questions?
Take home messages
The most important points to remember
when writing the Methods section are:
1. State exactly what you did, no more than that
2. Concentrate on the primary aim of the study,
not on the ancillary goals
3. Ensure reproducibility
Take home messages
When writing the Methods always
ask yourself in every step:
1. What has been done
2. How it has been done
3. When it has been done
4. Who did it
For further slides on these topics
please feel free to visit the
metcardio.org website:
http://www.metcardio.org/slides.html