Biostatistics PDF
Biostatistics PDF
Biostatistics: A Refresher
Kevin M. Sowinski, Pharm.D., FCCP
Purdue University College of Pharmacy
Indiana University School of Medicine
West Lafayette and Indianapolis, Indiana
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-351
Biostatistics: A Refresher
1. A randomized controlled trial assesses the effects 4. You are reading a manuscript that evaluates the
of the treatment of heart failure on global func- impact of obesity on enoxaparin pharmacokinet-
tioning in three groups of adults after 6 months of ics. The authors used an unpaired t-test to compare
treatment. Investigators wanted to assess global the baseline values of body mass index (BMI) in
functioning with the New York Heart Association normal subjects and obese subjects. You are eval-
(NYHA) functional classification, an ordered scale uating the use of an unpaired t-test to compare the
from I to IV, and to compare the patient classifi- BMI between the two groups. Which choice rep-
cation after 6 months of treatment. Which statisti- resents the most appropriate criteria to be met to
cal test is most appropriate to assess differences in use this parametric test?
functional classification between the groups?
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-352
Biostatistics: A Refresher
A.
The sample sizes in the normal and obese B. The new drug and active control appear to
subjects should be equal to allow the use of a be equally efficacious in increasing HDL-C
t-test. concentrations.
B. A t-test is not appropriate because BMI data C. The new drug is better than lifestyle modifica-
are ordinal. tions because it increases HDL-C concentra-
C. The variance of the BMI data has to be similar tions to a greater extent.
in each group. D. This study is potentially underpowered.
D. The prestudy power should be at least 90%.
7. Researchers planned a study to evaluate the per-
5. You are evaluating the results and discussion of a centage of subjects who achieved less than a tar-
journal club article to present to the pharmacy resi- get blood pressure (less than 140/90 mm Hg)
dents at your institution. The randomized, prospec- when initiating therapy with two different doses
tive, controlled trial evaluated the efficacy of a new of amlodipine. In the study of 100 subjects, the
controller drug for asthma. The primary end point amlodipine 5-mg group (n=50) and the amlodipine
was the morning forced expiratory volume in 1 10-mg group (n=50) were compared. The investi-
second (FEV1) in two groups of subjects (men and gators used a blood pressure goal as their primary
women). The difference in FEV1 between the two end point, defined as the percentage of subjects
groups was 15% (95% confidence interval [CI], who successfully achieved the blood pressure goal
10%21%). Which statement is most appropriate, at 3 months. Which is the most appropriate statisti-
given the results? cal test to answer such a question?
A. Without the reporting of a p-value, it is not A. Independent samples t-test.
possible to conclude whether these results B. Chi-square or Fisher exact test.
were statistically significant. C. Wilcoxon signed rank test.
B. There is a statistically significant difference D. One-sample t-test.
between the men and women (p<0.05).
C. There is a statistically significant difference 8. An investigational drug is being compared with
between the men and women (p<0.01). an existing drug for the treatment of anemia in
D. There is no statistically significant difference patients with chronic kidney disease. The study is
between the men and women. designed to detect a minimum 20% difference in
response rates between the groups, if one exists,
6. An early-phase clinical trial of 40 subjects evalu- with an a priori of 0.05 or less. The investigators
ated a new drug known to increase high-density are unclear whether the 20% difference between
lipoprotein cholesterol (HDL-C) concentrations. response rates is too large and think a smaller
The objective of the trial was to compare the new difference might be more clinically meaningful.
drugs ability to increase HDL-C with that of life- In revising their study, they decide they want to
style modifications (active control group). At the be able to detect a minimum 10% difference in
beginning of the study, the mean baseline HDL-C response. Which change to the study parameters is
was 37 mg/dL in the active control group and 38 most appropriate?
mg/dL in the new drug group. At the end of the A. Increase the sample size.
3-month trial, the mean HDL-C for the control B. Select an of 0.001 as a cutoff for statistical
group was 44 mg/dL and for the new drug group, significance.
49 mg/dL. The p-value for the comparison at 3
C. Select an of 0.10 as a cutoff for statistical
months was 0.08. Which statement provides the
significance.
best interpretation of these results?
D. Decrease the sample size.
A. An a priori of less than 0.10 would have
made the study more clinically useful.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-353
Biostatistics: A Refresher
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-354
Biostatistics: A Refresher
I. INTRODUCTION TO STATISTICS
B. Useful Tool for Quantifying Clinical and Laboratory Data in a Meaningful Way
C. Assists in Determining Whether and by How Much a Treatment or Procedure Affects a Group of Patients
G. Several Papers Have Investigated the Various Types of Statistical Tests Used in the Biomedical Literature;
the data from one of these papers are illustrated below. Tables 1 and 2 modified from: Windish DM, Huot
SJ, Green ML. Medicine residents understanding of the biostatistics and results in the medical literature.
JAMA 2007;298:1010-22.
Table 1. Statistical Content of Original Articles in The New England Journal of Medicine, 20042005
% of Articles % of Articles
Statistical Procedure Statistical Procedure
Containing Methods Containing Methods
No statistics or descriptive 13 Adjustment and standardization 1
statistics
t-Tests 26 Multiway tables 13
Contingency tables 53 Power analyses 39
Nonparametric tests 27 Cost-benefit analysis <1
Epidemiologic statistics 35 Sensitivity analysis 6
Pearson correlation 3 Repeated-measures analysis 12
Simple linear regression 6 Missing-data methods 8
Analysis of variance 16 Noninferiority trials 4
Transformation 10 Receiver operating characteristics 2
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-355
Biostatistics: A Refresher
Table 1. Statistical Content of Original Articles in The New England Journal of Medicine, 20042005 (continued)
% of Articles % of Articles
Statistical Procedure Statistical Procedure
Containing Methods Containing Methods
Nonparametric correlation 5 Resampling 2
Principal component and
Survival methods 61 2
cluster analyses
Multiple regression 51 Other methods 4
Multiple comparisons 23
Table 2. Statistical Content of Original Articles from Six Major Medical Journals from January to March 2005
(n=239 Articles)a
Statistical Test No. (%) Statistical Test No. (%)
Descriptive statistics (mean,
219 (91.6) Others
median, frequency, SD, and IQR)
Simple statistics 120 (50.2) Intention-to-treat analysis 42 (17.6)
Chi-square analysis 70 (29.3) Incidence or prevalence 39 (16.3)
t-test 48 (20.1) Relative risk or risk ratio 29 (12.2)
Kaplan-Meier analysis 48 (20.1) Sensitivity analysis 21 (8.8)
Wilcoxon rank sum test 38 (15.9) Sensitivity or specificity 15 (6.3)
Fisher exact test 33 (13.8)
Analysis of variance 21 (8.8)
Correlation 16 (6.7)
Multivariate analysis 164 (68.6)
Cox proportional hazards 64 (26.8)
Multiple logistic regression 54 (22.6)
Multiple linear regression 7 (2.9)
Other regression analysis 38 (15.9)
None 5 (2.1)
Articles published in American Journal of Medicine, Annals of Internal Medicine, BMJ, The Journal of the American Medical Association,
a
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-356
Biostatistics: A Refresher
A. Definition: Random VariablesA variable with observed values that may be considered outcomes of an
experiment and whose values cannot be anticipated with certainty before the experiment is conducted
C. Discrete Variables
1. Can take only a limited number of values within a given range
2. Nominal: Classified into groups in an unordered manner and with no indication of relative severity (e.g.,
male or female sex, mortality [dead or alive], disease presence [yes or no], race, marital status)
3. Ordinal: Ranked in a specific order but with no consistent level of magnitude of difference between
ranks (e.g., NYHA functional class describes the functional status of patients with heart failure, and
subjects are classified in increasing order of symptoms: I, II, III, IV; Likert-type scales)
4. Common error: Measure of central tendencyIn most cases, means and standard deviations (SDs)
should not be reported with ordinal data. What is a common incorrect use of means and SDs to show
ordinal data?
A. Descriptive Statistics: Used to summarize and describe data that are collected or generated in research stud-
ies. This is done both visually and numerically.
1. Visual methods of describing data
a. Frequency distribution
b. Histogram
c. Scatterplot
d. Boxplot
2. Numerical methods of describing data: Measures of central tendency
a. Arithmetic mean (i.e., average)
i. Sum of all values divided by the total number of values
ii. Should generally be used only for continuous and normally distributed data
iii. Very sensitive to outliers and tend toward the tail, which has the outliers
iv. Most commonly used and most understood measure of central tendency
v. Geometric mean
b. Median
i. Midpoint of the values when placed in order from highest to lowest. Half of the observations
are above and half are below. When there is an even number of observations, it is the mean of
the two middle values.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-357
Biostatistics: A Refresher
Table 3. Twenty Baseline HDL-C Concentrations from an Experiment Evaluating the Impact of Green Tea on HDL-C
64 60 59 65 64 62 54
54 68 67 79 55 48 65
59 65 87 49 46 46
HDL-C = high-density lipoprotein cholesterol.
a. Calculate the mean, median, and mode of the above data set.
b. Calculate the range, and SD (on examination you will not have to do this by hand).
c. Evaluate the visual presentation of the data.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-358
Biostatistics: A Refresher
B. Inferential Statistics
1. Conclusions or generalizations made about a population (large group) from the study of a sample of that
population
2. Choosing and evaluating statistical methods depend, in part, on the type of data used.
3. An educated statement about an unknown population is commonly referred to in statistics as an inference.
4. Statistical inference can be made by estimation or hypothesis testing.
A. Discrete Distributions
1. Binomial distribution
2. Poisson distribution
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-359
Biostatistics: A Refresher
f. Why is all this information about the difference between the SEM and SD worth knowing?
i. Calculation of CIs. (95% CI is approximately the mean 2 times the SEM.)
ii. Hypothesis testing
iii. Deception (e.g., makes results look less variable, especially when used in graphic format)
9. Recall the previous example about HDL-C and green tea. From the calculated values in section III, do
these data appear to be normally distributed?
V. CONFIDENCE INTERVALS
B. CIs Can Also Be Used for Any Sample Estimate. Estimates derived from categorical data such as risk, risk
differences, and risk ratios are often presented with the CI and will be discussed below.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-360
Biostatistics: A Refresher
A. Null and Alternative Hypotheses (see Table 4 for other types of examples)
1. Null hypothesis (H0): Example: No difference between groups being compared (treatment A equals
treatment B)
2. Alternative hypothesis (H A): Example: Opposite of null hypothesis; states that there is a difference
(treatment A does not equal treatment B)
3. The structure or the manner in which the hypothesis is written dictates which statistical test is used.
Two-sample t-test: H0: Mean 1 = Mean 2
4. Used to assist in determining whether any observed differences between groups can be explained by
chance
5. Tests for statistical significance (hypothesis testing) determine whether the data are consistent with H0
(no difference).
6. The results of the hypothesis testing will indicate whether enough evidence exists for H0 to be rejected.
a. If H0 is rejected: Statistically significant difference between groups (unlikely attributable to chance)
b. If H0 is not rejected: No statistically significant difference between groups (any apparent differ-
ences may be attributable to chance). Note that we are not concluding that the treatments are equal.
7. Types of hypothesis testing. These are situations in which two groups are being compared. There are
numerous other examples of situations these procedures could be applied to (Table 4).
B. To Determine What Is Sufficient Evidence to Reject H0: Set the a priori significance level () and generate
the decision rule.
1. Developed after the research question has been stated in hypothesis form
2. Used to determine the level of acceptable error caused by a false positive (also known as level of
significance)
a. Convention: A priori is usually 0.05.
b. Critical value is calculated, capturing how extreme the sample data must be to reject H0.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-361
Biostatistics: A Refresher
C. Parametric Tests
1. Student t-test: Several different types
a. One-sample test: Compares the mean of the study sample with the population mean
b. Two-sample, independent samples, or unpaired test: Compares the means of two independent sam-
ples. This is an independent samples test.
Group 1 Group 2
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-362
Biostatistics: A Refresher
Group 1
Measurement 1 Measurement 2
d. Common error: Use of multiple t-tests with more than two groups
2. Analysis of variance (ANOVA): A more generalized version of the t-test that can apply to more than
two groups
a. One-way ANOVA: Compares the means of three or more groups in a study; also known as single-
factor ANOVA. This is an independent samples test.
Related Measurements
Group 1 Measurement 1 Measurement 2 Measurement 3
D. Nonparametric Tests
1. These tests may also be used for continuous data that do not meet the assumptions of the t-test or
ANOVA.
2. Tests for independent samples
a. Wilcoxon rank sum test, Mann-Whitney U test, or Wilcoxon Mann-Whitney test: Compare two
independent samples (related to a t-test)
b. Kruskal-Wallis one-way ANOVA by ranks
i. Compares three or more independent groups (related to one-way ANOVA)
ii. Post hoc testing
3. Tests for related or paired samples
a. Sign test and Wilcoxon signed rank test: Compares two matched or paired samples (related to a
paired t-test)
b. Friedman ANOVA by ranks: Compares three or more matched or paired groups
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-363
Biostatistics: A Refresher
E. Nominal Data
1. Chi-square (2) test: Compares expected and observed proportions between two or more groups
a. Test of independence
b. Test of goodness of fit
2. Fisher exact test: Specialized version of the chi-square test for small groups (cells) containing less than
five predicted observations
3. McNemar: Paired samples
4. Mantel-Haenszel: Controls for the influence of confounders
2. Which is the appropriate statistical test to determine baseline differences in the following:
a. Sex distribution?
b. LDL-C?
c. Percentage of smokers and nonsmokers?
3. Which is the appropriate statistical test to determine the following:
a. The effect of alirocumab plus statins on LDL-C?
b. The primary end point?
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-364
Biostatistics: A Refresher
A. Type I Error: The probability of making this error is defined as the significance level .
1. Convention is to set the to 0.05, effectively meaning that, 1 in 20 times, a type I error will occur when
the H0 is rejected. So, 5.0% of the time, a researcher will conclude that there is a statistically significant
difference when one does not actually exist.
2. The calculated chance that a type I error has occurred is called the p-value.
3. The p-value tells us the likelihood of obtaining a given (or a more extreme) test result if the H0 is true.
When the level is set a priori, H0 is rejected when p is less than . In other words, the p-value tells us
the probability of being wrong when we conclude that a true difference exists (false positive).
4. A lower p-value does not mean the result is more important or more meaningful but only that it is sta-
tistically significant and not likely to be attributable to chance.
C. Power (1 )
1. The probability of making a correct decision when H0 is false; the ability to detect differences between
groups if one actually exists
2. Dependent on the following factors:
a. Predetermined
b. Sample size
c. The size of the difference between the outcomes you want to detect. Often not known before con-
ducting the experiment, so to estimate the power of your test, you will have to specify how large a
change is worth detecting
d. The variability of the outcomes that are being measured
e. Items c and d are generally determined from previous data or the literature.
3. Power is decreased by the following (in addition to the above criteria):
a. Poor study design
b. Incorrect statistical tests (use of nonparametric tests when parametric tests are appropriate)
4. Statistical power analysis and sample size calculation
a. Related to above discussion of power and sample size
b. Sample size estimates should be performed in all studies a priori.
c. Necessary components for estimating appropriate sample size
i. Acceptable type II error rate (usually 0.100.20)
ii. Observed difference in predicted study outcomes that is clinically significant
iii. The expected variability in item ii
iv. Acceptable type I error rate (usually 0.05)
v. Statistical test that will be used for primary end point
5. Statistical significance versus clinical significance
a. As stated earlier, the size of the p-value is not necessarily related to the clinical importance of the
result. Smaller values mean only that chance is less likely to explain observed differences.
b. Statistically significant does not necessarily mean clinically significant.
c. Lack of statistical significance does not mean that results are not clinically important.
d. When considering nonsignificant findings, consider sample size, estimated power, and observed
variability.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-365
Biostatistics: A Refresher
B. Pearson Correlation
1. The strength of the relationship between two variables that are normally distributed, ratio or interval
scaled, and linearly related is measured with a correlation coefficient.
2. Often referred to as the degree of association between the two variables
3. Does not necessarily imply that one variable is dependent on the other (regression analysis will do that)
4. Pearson correlation (r) ranges from 1 to +1 and can take any value in between:
1 0 +1
Perfect negative linear relationship No linear relationship Perfect positive linear relationship
5. Hypothesis testing is performed to determine whether the correlation coefficient is different from zero.
This test is highly influenced by sample size.
D. Spearman Rank Correlation: Nonparametric test that quantifies the strength of an association between two
variables but does not assume a normal distribution of continuous data. Can be used for ordinal data or
nonnormally distributed continuous data
E. Regression
1. A statistical technique related to correlation. There are many different types. For simple linear regres-
sion, one continuous outcome (dependent) variable and one continuous independent (causative) variable
2. Two main purposes of regression: Development of prediction model and accuracy of prediction
3. Prediction model: Making predictions of the dependent variable from the independent variable; Y = mx
+ b (dependent variable = slope independent variable + intercept)
4. Accuracy of prediction: How well the independent variable predicts the dependent variable. Regression
analysis determines the extent of variability in the dependent variable that can be explained by the
independent variable.
a. Coefficient of determination (r2) measured describing this relationship. Values of r2 can range from
0 to 1.
b. An r2 of 0.80 could be interpreted as saying that 80% of the variability in Y is explained by the
variability in X.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-366
Biostatistics: A Refresher
c. This does not provide a mechanistic understanding of the relationship between X and Y but rather
a description of how clearly such a model (linear or otherwise) describes the relationship between
the two variables.
d. Like the interpretation of r, the interpretation of r2 is dependent on the scientific arena (e.g., clinical
research, basic research, social science research) to which it is applied.
5. For simple linear regression, two statistical tests can be used.
a. To test the hypothesis that the y-intercept differs from zero
b. To test the hypothesis that the slope of the line is different from zero
6. Regression is useful in constructing predictive models. The literature is full of examples of predictions.
The process involves developing a formula for a regression line that best fits the observed data.
7. Like correlation, there are many different types of regression analysis.
a. Multiple linear regression: One continuous independent variable and two or more continuous
dependent variables
b. Simple logistic regression: One categorical response variable and one continuous or categorical
explanatory variable
c. Multiple logistic regression: One categorical response variable and two or more continuous or cat-
egorical explanatory variables
d. Nonlinear regression: Variables are not linearly related (or cannot be transformed into a linear
relationship). This is where our pharmacokinetic equations come from.
e. Polynomial regression: Any number of response and continuous variables with a curvilinear rela-
tionship (e.g., cubed, squared)
8. Example of regression
a. The following data are taken from a study evaluating enoxaparin use. The authors were interested
in predicting patient response (measured as antifactor Xa concentrations) from the enoxaparin dose
in the 75 subjects who were studied.
1.20
1.00
Antifactor Xa Concentrations (U/mL)
0.80
0.60
0.40
0.20
0.00
0.00 1.00 2.00 3.00 4.00
Enoxaparin Dose (mg/Kg)
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-367
Biostatistics: A Refresher
b. The authors performed regression analysis and reported the following: Slope: 0.227, y-intercept:
0.097, p<0.05, r2 = 0.31.
c. Answer the following questions:
i. What are the assumptions necessary to use regression analysis?
ii. Provide an interpretation of the coefficient of determination.
iii. Predict antifactor Xa concentrations at enoxaparin doses of 2 and 3.75 mg/kg.
iv. What does the p<0.05 value indicate?
X. SURVIVAL ANALYSIS
A. Studies the Time Between Entry in a Study and Some Event (e.g., death, myocardial infarction)
1. Censoring makes survival methods unique; considers that some subjects leave the study for reasons
other than the event (e.g., lost to follow-up, end of study period)
2. Considers that all subjects do not enter the study at the same time
3. Standard methods of statistical analysis such as t-tests and linear or logistic regression may not be
appropriately applied to survival data because of censoring.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-368
Biostatistics: A Refresher
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-369
Biostatistics: A Refresher
REFERENCES
1.
Crawford SL. Correlation and regression. 13. Jones SR, Carley S, Harrison M. An introduction
Circulation 2006;114:2083-8. to power and sample size estimation. Emerg Med J
2.
Davis RB, Mukamal KJ. Hypothesis testing: 2003;20:453-8.
means. Circulation 2006;114:1078-82. 14. Kier KL. Biostatistical methods in epidemiology.
3.
DeYoung GR. Understanding biostatistics: an Pharmacotherapy 2011;31:9-22.
approach for the clinician. In: Zarowitz B, Shumock 15.
Kusuoka H, Hoffman JIE. Advice on statisti-
G, Dunsworth T, et al., eds. Pharmacotherapy Self- cal analysis for circulation research. Circ Res
Assessment Program, 5th ed. Kansas City, MO: 2002;91:662-71.
ACCP, 2005:1-20. 16.
Larson MG. Analysis of variance. Circulation
4.
DiCenzo R, ed. Clinical Pharmacists Guide to 2008;117:115-21.
Biostatistics and Literature Evaluation. Lenexa, 17. Larson MG. Descriptive statistics and graphical
KS: ACCP, 2015. displays. Circulation 2006;114:76-81.
5. Gaddis ML, Gaddis GM. Introduction to biosta- 18.
Overholser BR, Sowinski KM. Biostatistics
tistics, part 1: basic concepts. Ann Emerg Med primer, part 1. Nutr Clin Pract 2007;22:629-35.
1990;19:86-9.
19.
Overholser BR, Sowinski KM. Biostatistics
6. Gaddis ML, Gaddis GM. Introduction to biostatis- primer, part 2. Nutr Clin Pract 2008;23:76-84.
tics, part 2: descriptive statistics. Ann Emerg Med
20.
Rao SR, Schoenfeld DA. Survival methods.
1990;19:309-15.
Circulation 2007;115:109-13.
7. Gaddis ML, Gaddis GM. Introduction to biosta-
21.
Rector TS, Hatton RC. Statistical concepts and
tistics, part 3: sensitivity, specificity, predictive
methods used to evaluate pharmacotherapy. In:
value, and hypothesis testing. Ann Emerg Med
Zarowitz B, Shumock G, Dunsworth T, et al., eds.
1990;19:591-7.
Pharmacotherapy Self-Assessment Program, 2nd
8. Gaddis ML, Gaddis GM. Introduction to biosta- ed. Kansas City, MO: ACCP, 1997:130-61.
tistics, part 4: statistical inference techniques in
22.
Strassels SA. Biostatistics. In: Dunsworth
hypothesis testing. Ann Emerg Med 1990;19:820-5.
TS, Richardson MM, Chant C, et al., eds.
9. Gaddis ML, Gaddis GM. Introduction to biosta- Pharmacotherapy Self-Assessment Program, 6th
tistics, part 5: statistical inference techniques for ed. Lenexa, KS: ACCP, 2007:1-16.
hypothesis testing with nonparametric data. Ann
23. Sullivan LM. Estimation from samples. Circulation
Emerg Med 1990;19:1054-9.
2006;114:445-9.
10. Gaddis ML, Gaddis GM. Introduction to biostatis-
24. Tsuyuki RT, Garg S. Interpreting data in cardiovas-
tics, part 6: correlation and regression. Ann Emerg
cular disease clinical trials: a biostatistical toolbox.
Med 1990;19:1462-8.
In: Richardson MM, Chant C, Cheng JWM, et al.,
11.
Harper ML. Biostatistics for the clinician. In: eds. Pharmacotherapy Self-Assessment Program,
Zarowitz B, Shumock G, Dunsworth T, et al., eds. 7th ed. Lenexa, KS: ACCP, 2010:241-55.
Pharmacotherapy Self-Assessment Program, 4th
25. Windish DM, Huot SJ, Green ML. Medicine resi-
ed. Kansas City, MO: ACCP, 2002:183-200.
dents understanding of the biostatistics and results
12. Hayney MS, Meek PD. Essential clinical concepts in the medical literature. JAMA 2007;298:1010-22.
of biostatistics. In: Carter BL, Lake KD, Raebel
MA, et al., eds. Pharmacotherapy Self-Assessment
Program, 3rd ed. Kansas City, MO: ACCP,
1999:19-46.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-370
Biostatistics: A Refresher
1. Answer: A 4. Answer: C
The NYHA functional class is an ordinal scale from Sample sizes need not be equal to use a t-test (Answer
I (no symptoms) to IV (severe symptoms). Neither A is incorrect). Body mass index data are not ordinal
ANOVA nor ANCOVA is appropriate for ordinal or but continuous; thus, a t-test is appropriate (Answer
noncontinuous data (Answer C and Answer D are incor- B is incorrect). The assumption of equal variances is
rect). The Wilcoxon signed rank test is an appropriate required to use any parametric test (Answer C is cor-
nonparametric test to use for paired ordinal data, such rect). A specific value for power is not required to use a
as the change in NYHA functional class over time on test (Answer D is incorrect).
the same person (Answer B is incorrect). The Kruskal-
Wallis test is the nonparametric analog of a one-way 5. Answer: B
ANOVA and is appropriate for this analysis (Answer The reporting of the mean difference and CI is thought
A is correct). by many to be a superior means of presenting the results
from a clinical trial because it describes both precision
2. Answer: C and statistical significance, as compared with a p-value,
You cannot determine which finding is more important which distills everything into one value, making
(in this case, the best drug) on the basis of the p-value Answer A incorrect. The presentation of the data in this
(i.e., a lower p-value does not mean more important) manner clearly shows all the necessary information for
(Answer B is incorrect). All statistically significant making the appropriate conclusion. To assess statistical
results are interpreted as significant without respect to significance by use of CIs, the 95% CI (corresponding
the size of the p-value. This trial had four independent to the 5% type I error rate used in most studies) may
samples, and use of the unpaired (independent sam- not contain zero (signifying no difference between men
ples) t-test is not appropriate because it requires several and women) for the mean difference, making Answer
unnecessary tests and increases the chances of making D incorrect. Answer B is correct because the p-value of
a type I error (Answer A is incorrect). In this setting, less than 0.05 corresponds to the 95% CI in that item.
ANOVA is the correct test (Answer C is correct), fol- To evaluate Answer C, we would need to know the
lowed by a multiple-comparisons procedure to deter- 99% CI.
mine where the actual differences between groups lie.
A paired t-test is inappropriate because this is a par- 6. Answer: D
allel-group trial (Answer D is incorrect). The use of Answer A is incorrect because it uses unconven-
ANOVA in this case assumes a normal distribution and tional approaches to determine statistical significance.
equal variance in each of the four groups. Although this can be done, it is unlikely to be accepted
by other readers and investigators. This study observed
3. Answer: D a nonsignificant increase in HDL-C concentration
The typical a priori alpha error (type I) rate is 5% between the two groups. With a small sample size, such
(i.e., when the study was designed, the error rate was as the one used in this study, there is always concern
designed to be 5% or less) (Answer D is correct). The about adequate power to observe a difference between
actual type I error rate is reported in the question as 0.01 the two treatments. A difference may exist between
(1%) (Answer A is incorrect). Answer B and Answer C these two drugs, but the number of subjects studied may
are related; the study did have enough power because be too small to detect it statistically. Answer D is cor-
a statistically significant difference was observed. rect because, with the lack of information provided in
Similarly, a type II error was not made because this this narrative, it is not possible to estimate power; thus,
error has to do with not finding a difference when one more information is needed. Answer B may be correct,
truly exists. In this question, the type I error rate is 1%, but without first addressing the question of adequate
the value of the p-value. power, it would be an inappropriate conclusion to draw.
Answer C is incorrect because even though the new drug
increased HDL-C concentration more than the other
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-371
Biostatistics: A Refresher
8. Answer: A
Detecting the smaller difference between the treat-
ments requires more power. Power can be increased
in several different ways. Answer A is correct because
the most common approach is to increase the sample
size, which is expensive for the researchers. Answer
D is incorrect because smaller sample sizes diminish
a studys ability to detect differences between groups.
Power can also be increased by increasing , but doing
so increases the chances of a type I error. Answer B
decreases , thus making it more difficult to detect dif-
ferences between groups. Answer C certainly makes it
easier to detect a difference between the two groups,
but it uses an unconventional value and is thus not the
most appropriate technique.
ACCP Updates in Therapeutics 2016: Pharmacotherapy Preparatory Review and Recertification Course
1-372