Information for Authors  General Statistical Guidance
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1. Presentation
Issue

Reporting Guideline

Percentages

Report percentages to one decimal place (i.e., xx.x%) when sample
size is =200.
To avoid the appearance of a level of precision that is not present with
small samples, do not use decimal places (i.e., xx%, not xx.xx%) when sample
size is < 200.

Standard
deviations

Use “mean (SD)” rather than “mean ± SD” notation. The ± symbol is
ambiguous and can represent standard deviation or standard error.

Standard
errors

Report confidence intervals, rather than standard errors, when possible.

P values

For P values between 0.001 and 0.20, please report the value
to the nearest thousandth. For P values greater than 0.20, please
report the value to the nearest hundredth. For P values less than
0.001, report as “P<0.001.”

“Trend”

Use the word trend when describing a test for trend or
doseresponse.
Avoid the term trend when referring to P values near but not
below 0.05. In such instances, simply report a difference and the confidence
interval of the difference (if appropriate) with or without the P
value.

Statistical software

Specify in the statistical analysis section the statistical
software—version, manufacturer, and the specific functions,
procedures, or programs—used for analyses.

Cox models

When reporting findings from Cox proportional hazards models:
 Do not describe hazard ratios as relative risks.
 Do report how the assumption of proportional hazards was tested, and
what the test showed.

Descriptive
tables

In tables that simply describe the characteristics of 2 or more groups
(e.g., Table 1 of a clinical trial):
 Report averages with standard deviations, not standard errors, when data
are normally distributed.
 Report median (minimum, maximum) or median (25^{th},
75^{th} percentile [interquartile range, or IQR] when data are not
normally distributed.
 Avoid reporting P values as there can be imbalance when P
values are not significant (because of small sample size) and balance when
P values are significant (because of large sample size).

Tables reporting multivariable analyses

Authors sometimes present tables that compare one by one an outcome
with multiple individual factors followed by a multivariable analysis that
adjusts for confounding. If confounding is present, as is often the case, the
oneway comparisons are simply intermediate steps that offer little useful
information for the reader. In general, omit presenting these intermediate
steps in the manuscript and do not focus on them in the Results or
Discussion.

Figures

When developing informative graphics, follow these simple rules of thumb:
 Avoid pie charts.
 Avoid simple bar plots that do not present measures of variability.
 For metaanalysis forest plots, provide the raw data (numerators and
denominators) in the margins.
 For survival plots, provide the numbers of people at risk by group and time
below the horizontal axis.

2. Multivariable Analysis
Screening covariates
Approaches that select factors for inclusion in a multivariable model
only if the factors are “statistically significant” in
“bivariate screening” are not optimal. A factor can be a
confounder even if it is not statistically significant by itself because it
changes the effect of the exposure of interest when it is included in the
model, or because it is a confounder only when included with other
covariates.
Useful resource:
 Sun GW, Shook TL, Kay GL. Inappropriate use of bivariable analysis to
screen risk factors for use in multivariable analysis. J Clin Epidemiol.
1996;49:90716. PMID: 8699212
Model building
Authors should avoid stepwise methods of model building, except for the
narrow application of hypothesis generation for subsequent studies.
Stepwise methods include forward, backward, or combined procedures for the
inclusion and exclusion of variables in a statistical model based on
predetermined P value criteria. Better strategies than P
value driven approaches for selecting variables are those that use external
clinical judgment. Authors might use a bootstrap procedure to determine
which variables, under repeated sampling, would end up in the model using
stepwise variable selection procedures. Regardless, authors should tell
readers how model fit was assessed, how and which interactions were
explored, and the results of those assessments.
Useful resources:
 Collett D, Stepniewska K. Some practical issues in binary data
analysis. Statist Med. 1999;18:220921. PMID: 10474134
 Mickey RM, Greenland S. The impact of confounder selection criteria on
effect estimation. Am J Epidemiol. 1989;129:12537. PMID: 2910056
 Steyerberg EW, Eijkemans MJC, Harrell FE, Jr., Habbema JDF. Prognostic
modeling with logistic regression analysis: a comparison of selection and
estimation methods in small data sets. Statist Med. 2000;19:105979.
PMID: 10790680
 Steyerberg EW, Eijkemans MJC, Habbema DF. Stepwise selection in small
data sets: a simulation study of bias in logistic regression analysis. J
Clin Epidemiol. 1999;52:93542. PMID: 10513756
 Altman D, Andersen PK. Bootstrap investigation of the stability of a
Cox regression model. Statist Med. 1989;8:77183. PMID:2672226
 Mick R, Ratain MJ. Bootstrap validation of pharmacodynamic models
defined via stepwise linear regression. Clin Pharmacol Ther.
1994;56:21722. PMID: 8062499
 Harrell FE, Jr, et al. Multivariable prognostic models: issues in
developing models, evaluating assumptions and adequacy, and measuring and
reducing errors. Statist Med. 1996;15:36187. PMID: 8668867
3. Measurement Error
If several risk factors for disease are considered in a logistic
regression model and some of these risk factors are measured with error,
the point and interval estimates of relative risk corresponding to any of
these factors may be biased either toward or away from the null value; the
direction of bias is never certain. In addition to potentially biased
estimates, confidence intervals of correctly adjusted estimates will be
wider, sometime substantially, than naïve confidence intervals.
Authors are encouraged to consult the references below for strategies to
address this problem.
Useful resources:
 Rosner B, Spiegelman D, Willett WC. Correction of logistic regression
relative risk estimates and confidence intervals for measurement error: the
case of multiple covariates measured with error. Am J Epidemiol.
1990;132:73445. PMID: 2403114
 Carroll R. Measurement Error in epidemiologic studies. In Encyclopedia
of Biostatistics. New York: John Wiley & Sons; 1998. ISBN: 0471975761.
4. Measures of Effect and Risk
Clinically meaningful estimates
Authors should report results for meaningful metrics rather than
reporting raw results. For example, rather than reporting the log odds
ratio from a logistic regression, authors should transform coefficients
into the appropriate measure of effect size, odds ratio, relative risk, or
risk difference. Estimates, such as an odds ratio or relative risk, should
not be reported for a 1unit change in the factor of interest if a 1unit
change lacks clinical meaning (age, mm Hg of blood pressure, or any other
continuous or interval measurement with small units). All estimates should
reflect a clinically meaningful change, along with 95% confidence
bounds.
Betweengroup differences
For comparisons of interventions (e.g., trials), focus on between group
differences, with 95% confidence intervals of the differences, and not on
withingroup differences. State the results using absolute numbers
(numerator/denominator) when feasible. When discussing effects, refer to
the confidence intervals rather than P values and point out for
readers if the confidence intervals exclude the possibility of significant
clinical benefit or harm.
Odds ratios and predicted probabilities
Authors often report odds ratios for multivariable results when the odds
ratio is difficult to interpret or not meaningful. First, the odds ratio
might overstate the effect size when the reference risk is high. For
example, if the reference risk is 25% (odds = 0.33) and the odds ratio is
3.0, the relative risk is only 2.0. Statements such as “3fold
increased risk” or “3 times the risk” are incorrect.
Second, readers want an easily understood measure of the level of risk (and
the confidence intervals) for different groups of patients as defined by
treatment, exposure, and covariates. Consider providing a table of
predicted probabilities for each of the factors of interest, and confidence
intervals of those predicted probabilities. Moreover, a multiway table that
crossclassifies predicted probabilities by the most important factor and
then adjusts for the remaining factors will often be more meaningful than a
table of adjusted odds ratios. Standard commercial software can produce
predicted probabilities and confidence bounds.
Useful resource:
 Altman DG, Deeks JJ, Sackett DL. Odds ratios should be avoided when
events are common. BMJ. 1998;317:1318. PMID: 9804732
5. Missing Data
Missing variables
Always report the frequency of missing variables and how the analysis
handled missing data. Consider adding a column to tables or a row under
figures that makes clear the amount of missing data. Avoid using a simple
indicator or dummy variable to represent a missing value. Replacing missing
predictors with dummy variables or missing indicators generally leads to
biased estimates.
Useful resources:
 Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, et al.
Multiple imputation for missing data in epidemiological and clinical
research: potential and pitfalls. BMJ. 2009;338:b2393. PMID: 19564179
 Vach W, Blettner M. Biased estimation of the odds ratio in casecontrol
studies due to the use of ad hoc methods or correcting for missing values
of confounding variables. Am J Epidemiol. 1991;134:895907. PMID:
1670320
 Vach W, Blettner M. Missing data in epidemiologic studies. In
Encyclopedia of Biostatistics. New York: John Wiley & Sons; 1998:264154.
ISBN: 0471975761
 Greenland S, Finkle WD. A critical look at methods for handling missing
covariates in epidemiologic regression analyses. Am J Epidemiol.
1995;142:125564. PMID: 7503045
 Allison PD. Missing Data. Thousand Oaks, California: Sage Publications;
2002. ISBN: 0761916725
Missing Outcomes
Always report the frequency of missing outcomes and followup data,
reasons and any patterns for the missing data, and how you handled missing
data in the analyses. Do not use a last observation carried forward
approach (LOCF) to address incomplete followup even if the original
protocol prespecified that approach for handling missing data. LOCF
approaches understate variability and result in bias. The direction of the
bias is not predictable. Although the method of addressing missing data may
have little import on findings when the proportion of missing data is small
(e.g., <5%), authors should avoid using outdated or biased methods to
address incomplete followup. Appropriate methods for handling missing data
include imputation, patternmixture (mixed) models, and selection models.
Application of these methods requires consideration of the patterns and
potential mechanisms behind the missing data.
Useful resources:
 Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. New
York: John Wiley & Sons; 2011: chapters 17 and 18. ISBN:
0470380277
 Molenberghs G, Kenward MG. Missing Data in Clinical Studies. London:
John Wiley & Sons; 2007. ISBN: 0470849811
 Molenberghs G, Verbeke G. Models for Discrete Longitudinal Data. New
York: Springer; 2005: chapters 2632. ISBN: 0387251448
 National Research Council. The Prevention and Treatment of Missing Data
in Clinical Trials. Panel on Handling Missing Data in Clinical Trials.
Committee on National Statistics, Division of Behavioral and Social
Sciences and Education. Washington, DC: The National Academies Press; 2010.
ISBN: 0309158145 www.nap.edu/catalog/12955.html
6. Longitudinal Analyses
Consider using longitudinal analyses if outcome data were collected at
more than 1 time point. With an appropriate model for longitudinal
analysis, you can report differences within groups over time, differences
between groups, and differences across groups of their withingroup changes
over time (usually the key contrast of interest). You can control for any
confounding that might emerge, such as a difference in a variable (e.g.,
body weight) among those who remained in the study until completion.
Longitudinal analysis options include a population averaged analysis
(generalized estimating equations [GEEs], for example) that estimates the
time by treatment interaction and adjusts variance for the repeated
measures within individuals over time. Another option is a mixed effects
model, with random effects for patient, and the estimate of interest being
the time by treatment interaction. In choosing a model, consider whether
any missing data are missing at random (i.e., “ignorable”
missing data) or missing dependent on the observed data (i.e., informative
missing data). In GEE analyses, missing data are assumed to be missing
completely at random independent of both observed and unobserved data. In
random coefficient analysis, missing data are assumed missing at random
dependent on observed data but not on unobserved data.
Useful resources:
 Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. New
York: John Wiley & Sons; 2011. ISBN: 0470380277.
 Singer JD, Willett JB. Applied Longitudinal Data Analysis. New York:
Oxford University Press; 2003. ISBN: 0195152964.
 Twisk JWR. Applied Longitudinal Data Analysis for Epidemiology: A
Practical Guide. New York: Cambridge University Press; 2003 ISBN:
0521819768.
7. Figures and Tables
The following references give useful information about the design and
format of informative tables and figures:
 Tufte ER. The Visual Display of Quantitative Information. Cheshire CT:
Graphic Press; 1983: 178. ISBN: 0961392142
 Wainer, H. How to display data badly. The American Statistician.
1984;38:13747.
 Wainer H. Visual Revelations: Graphical Tales of Fate and Deception
From Napoleon Bonaparte to Ross Perot. New Jersey: Lawrence Erlbaum
Associates.;1997. ISBN: 038794902X
 Pocock SJ, Clayton TC, Altman DG. Survival plots of timetoevent
outcomes in clinical trials: good practice and pitfalls. Lancet
2002;359:168689. PMID: 12020548
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