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Techniques

A Review of Basic Biostatistics


Kimberly A. Dukes1,* and Lisa M. Sullivan2
1
DM-STAT, Incorporated, 1 Salem Street, Malden, MA 02148, USA
2
Department of Biostatistics, Boston University School of Public Health, 715 Albany Street, Boston, MA 02118, USA
*Correspondence: kim.dukes@dmstat.com

Introduction ber of categories. Each response is classified into one of


The appropriate statistical analysis depends on the several possible categories. The categories can be ordered
research question of interest, the study design, and the or unordered, and these are called ordinal and categorical
nature of the variables being examined. In this paper, we or nominal variables, respectively. Obesity status (normal,
review basic biostatistical procedures. We describe the overweight, or obese) is an example of an ordinal variable;
procedures in some detail and provide references for gender is an example of a nominal variable (male, female).
interested readers. We then discuss sample size require-
ments, which are critical in both designing studies and in Descriptive Statistics
interpreting research results. Descriptive statistics for continuous variables should
There are two phases to statistical analysis: descriptive always include a measure of location (e.g., a typical value)
statistics and statistical inference. As the names would and also a measure of variability. In most situations, the
suggest, descriptive statistics are used to describe mean is the appropriate measure of a typical value and
key study variables, whereas statistical inference is the standard deviation is the appropriate measure of vari-
employed to make generalizations or to draw inferences ability. However, there are exceptions. When a variable
about larger populations based on study data. is subject to extreme values, the mean may be artificially
In every study, we develop a statistical analysis plan to inflated or deflated depending on whether the extremes are
match specific study objectives. The objectives should on the high or low ends of the distribution. In the presence
be focused on one or several primary outcome variables. of extremes, the standard deviation can also be inflated.
The simplest study has one primary outcome variable In this situation, a more appropriate measure of a typical
and the appropriate descriptive statistics depend on the value is the median (i.e., the value that holds 50% of the
nature of that primary outcome variable. The appropriate values above it and 50% of the values below it). The median
procedures for statistical inference also depend on the is unaffected by extremes. When there are extremes, the
distribution of the primary outcome as well as the num- interquartile range or difference between the third (Q3) and
ber of comparison groups involved and whether these first (Q1) quartiles (i.e., Q3 − Q1) is the appropriate measure
groups are related (i.e., independent versus matched/ of variability. Determining whether there are extremes in
paired). Each of these issues is described below. the data becomes important in determining which statis-
tics are most appropriate to describe the primary outcome.
Classification of the Primary Outcome There are several guidelines that are used for determin-
For analytic purposes, variables are classified as continu- ing extremes (D’Agostino et al., 2004). A popular guideline
ous or discrete. Continuous variables, sometimes called suggests that extremes are values that are either below
quantitative or measurement variables, assume any value Q1 − 1.5 (Q3 − Q1) or above Q3 + 1.5 (Q3 − Q1). Descrip-
between a theoretical minimum and maximum. Examples tive statistics for discrete variables include the number and
include protein expression levels and serum biomarkers. proportions (or percentages) of respondents or sampling
Discrete variables can be thought of as having a fixed num- units in each response category.

Table 1. Descriptive Statistics by Obesity Statusa


Characteristic Normal Weight (n = 20) Overweight (n = 20) Obese (n = 20)
Age (years) 50.2 ± 7.3 51.8 ± 6.9 52.1 ± 7.1
Women (%) 42.8 48.1 53.6
Systolic blood pressure (mmHg) 124.9 ± 17.1 128.7 ± 16.3 131.4 ± 15.9
Diastolic blood pressure (mmHg) 80.4 ± 9.1 82.2 ± 8.7 84.9 ± 7.9
Triglycerides (mg/dl) 115.2 ± 88.9 117.6 ± 85.8 122.5 ± 89.2
Diabetes (%) 4.6 5.1 7.4
Total/HDL cholesterol ratio 4.7 ± 1.6 4.5 ± 1.5 4.2 ± 1.9
Means ± standard deviations or percentages.
a
Normal weight, body mass index (BMI) < 25; overweight, BMI 25.0–29.9; obese, BMI ≥ 30.

50  ©2008 Elsevier Inc. All rights reserved.


Techniques

Figure 1. Box-and-Whisker Plot for Serum RBP4 by Obesity


Status
Normal weight, BMI < 25; overweight, BMI 25.0–29.9; obese, BMI Figure 2. Bar Chart for Diabetes by Obesity Status
≥ 30. The data in these figures are hypothetical and are used for Normal weight, BMI < 25; overweight, BMI 25.0–29.9; obese, BMI ≥ 30.
­illustration purposes only.
and-whisker plots are most appropriate for continuous
Table 1 contains summary statistics on participants in outcomes, whereas histograms and bar charts are appro-
a study to assess the association between serum retinol priate for ordinal and categorical outcomes, respectively.
binding protein (RBP4) and obesity status. Means and Figure 1 is a side-by-side box-and-whisker plot display-
standard deviations are presented for continuous charac- ing the distribution of serum RBP4 in each obesity group.
teristics and percentages for discrete characteristics. Note The “box” contains the middle 50% of the distribution (i.e.,
the large standard deviation relative to the mean for trig- Q1 is the bottom of the box and Q3 is the top of the box) and
lycerides in each group, suggesting that the distribution of the median is the horizontal line in between. The range of
triglycerides is not symmetric. For the normal distribution, the data (minimum to maximum) is indicated by the vertical
the range (minimum to maximum) is approximately equal to line. The serum RBP4 levels increase by obesity status.
the mean plus or minus three standard deviations. In this Histograms are appropriate to display information on
case, it would be more appropriate to present medians and ordinal outcomes, and bar charts are appropriate for cat-
interquartile ranges for triglycerides. egorical outcomes. Figure 2 displays the increasing pro-
When preparing tables, it is important to limit the num- portions of diabetics by obesity status.
ber of decimal places so as not to overstate the preci- Graphical displays are also extremely useful for
sion in the analysis (typically one decimal place more describing associations. Scatter plots are appropri-
than the original unit of measurement). In addition, the ate when both variables are continuous. Figure 3 is
sample sizes should always be provided, as should the a scatter plot showing the association between body
scale or units of measurement for each characteristic. mass index (BMI) and serum RBP4. Figure 4 displays
the mean serum RBP4 levels by obesity status. The
Graphical Displays bars represent the means and the error bars show
Graphical displays are extremely powerful to illustrate the standard errors. Standard errors reflect sampling
distributions of responses or to show associations. Box- variability or variation in the means and are appropri-

Figure 3. Scatter Plot Showing Association between BMI Figure 4. Mean RBP4 by Obesity Status
and Serum RBP4 Normal weight, BMI < 25; overweight, BMI 25.0–29.9; obese, BMI ≥ 30.

©2008 Elsevier Inc. All rights reserved.  51


Techniques

ate when comparing means among groups. (Standard approaches are based on different assumptions and
deviations summarize variability in individual scores.) can have different interpretations. The assumptions
Note the contrast between Figures 1 and 4. Figure 1 for each procedure are important. If assumptions are
displays the distribution of individual serum RBP4 lev- not met, then procedures will fail to maintain desirable
els, whereas Figure 4 displays summary statistics on statistical properties (e.g., confidence intervals will not
serum RBP4 levels by obesity status. The most appro- maintain claimed probabilities, and hypothesis tests
priate display depends on the objective (e.g., to dem- may be more likely to produce incorrect results). Some
onstrate variability in individual scores or to compare assumptions are extremely important and others can
means among groups). be relaxed. An important assumption is independence
of sampling units. Some procedures are based on the
Unit of Analysis assumption that the outcome of interest is approxi-
The unit of analysis refers to the entity on which mea- mately normally distributed. Many techniques maintain
surements are made. In clinical studies, the unit of their statistical properties in the presence of violations
analysis is often the individual. Some studies may of this assumption. We will indicate the situations in
measure a particular characteristic or biomarker in the which this assumption is important.
same individual repeatedly over time. Statistical pro- There are two general areas of statistical inference—
cedures assume independence of the units of analy- estimation and hypothesis testing. In estimation, we
sis. Thus, in study designs where units are measured generate confidence interval (CI) estimates of unknown
repeatedly over time, the analyses must reconcile population parameters (e.g., the mean in a single popu-
these dependencies. lation, the difference in proportions in two independent
samples) based on sample data appropriately accounting
Number of Comparison Groups and Relationships for sampling variability. Confidence interval estimates are
among Groups interpreted as a range of plausible values for an unknown
In many statistical applications, it is of interest to com- population parameter with a probability attached (Sul-
pare groups on the basis of the primary outcome(s). For livan, 2006). In hypothesis testing, we formally compare
example, we might want to compare characteristics population parameters based on sample data, again
shown in Table 1 by obesity status. The nature of the accounting for sampling variability. We set up competing
primary outcome dictates how the comparison will be hypotheses, called the null and research hypotheses. The
made. If the primary outcome is continuous, then means null hypothesis is the no-difference or no-effect state-
(e.g., mean ages, blood pressures) or medians (e.g., ment, whereas the research hypothesis states the antici-
median triglycerides) are compared among groups. If pated or hypothesized difference or effect. A test statistic
the primary outcome is discrete (e.g., gender or diabetes is computed which summarizes the sample information
status), then proportions are compared among groups. as it relates to the null hypothesis. Hypothesis tests pro-
The number of comparison groups is important in duce a p value, which is the probability of observing a test
determining the appropriate statistical test. One-group statistic as large or larger than that observed if the null
or one-sample procedures are used to compare a single hypothesis were true (D’Agostino et al., 2004). A small p
study sample to a known referent (e.g., a historical com- value (e.g., p value < 0.05) would suggest that there is less
parator). Two-group or two-sample procedures are very than a 5% probability of observing a difference as large or
popular and can be used, for example, to compare com- larger than that observed in the study sample, and would
peting treatments (e.g., active drug versus placebo). A likely lead to rejection of the null hypothesis in favor of the
critically important issue is whether the groups are inde- research hypothesis. The investigator must choose the
pendent or matched/paired. Independent groups are appropriate significance criterion on which to make that
physically separate and are comprised of distinct sam- decision (e.g., 0.05, 0.01). Both significant (i.e., p value <
pling units (e.g., different experimental units assigned 0.05) and nonsignificant p values should be provided so
to the active drug versus placebo), whereas dependent, that the reader can judge the significance (or lack thereof)
matched, or paired groups are often produced when the of the findings.
same sampling units are measured twice (e.g., before and
after an exposure) or when the sampling units are paired Procedures for Statistical Inference
(e.g., siblings, litter mates). In these situations, proce- We now describe popular procedures for statisti-
dures are needed to appropriately account for within- cal inference. Investigators must choose whether a
subject variability. This is discussed further below. confidence interval approach or a hypothesis testing
approach is appropriate in a given setting. We provide
Statistical Inference some examples below to illustrate the difference in
There are many procedures that are used for statis- approaches.
tical inference. Each procedure has assumptions One-Sample Procedures for Means and Proportions
about the design and about the distribution of the As noted above, there are one-sample procedures for
primary outcome. It is important to recognize that means and proportions. One-sample studies are most
there are often several ways to analyze data. Different useful when investigating new techniques or technolo-

52  ©2008 Elsevier Inc. All rights reserved.


Techniques

Table 2. Confidence Intervals for the Population


dichotomous response categories. If there are fewer
Mean and Population Proportion
than five sampling units in one or both of the response
categories, then an exact procedure should be used
CI for population meana s
x t (Agresti, 2002).
n
Using the data summarized in Table 1, a 95% confi-
CI for population proportion b
p̂(1 p̂) dence interval for the mean Total/HDL cholesterol ratio
p̂ z
n for participants of normal weight is 4.7 ± 0.7 or (4.0, 5.4).
Thus, we are 95% confident that the true mean Total/
a
Where x is the mean in the study sample, t is the value from
the t distribution reflecting the desired confidence level (e.g., HDL cholesterol ratio for participants of normal weight
95%), s is the standard deviation in the study sample, and n is between 4.0 and 5.4. In the confidence interval, 4.7 is
is the sample size. the mean and 0.7 is the margin of error. The margin of
s error is the product of the t value reflecting the desired
is the standard error (or variability of the sample mean).
n confidence level (95%) and the standard error. Ninety-
b
where p̂ is the proportion in the study sample, z is the value five percent confidence intervals for the mean Total/HDL
from the standard normal distribution reflecting the desired cholesterol ratio for overweight and obese participants
confidence level, and n is the sample size. are (3.8, 5.2) and (3.3, 5.1), respectively.
Using the data summarized in Table 1, a 95% confi-
dence interval for the proportion of diabetics among
gies and a confidence interval estimate for an unknown
obese participants is (0%–19%). This confidence interval
mean or proportion based on the study sample can be
is wide due to the small sample size (n = 20).
very valuable. The confidence interval estimate pro-
In the hypothesis testing approach, a one-sam-
vides a range of plausible values for the unknown mean
ple test can be used, for example, to compare the
or proportion that can be useful, for example, in plan-
observed mean in a study sample to a known mean or
ning future studies (e.g., comparative studies).
the observed proportion in a study sample to a known
The formulas for confidence intervals for the popu-
proportion when the primary outcome is continuous
lation mean and population proportion are shown in
or dichotomous, respectively. For example, suppose
Table 2. The formula for the confidence interval for
a study reports a mean serum RBP4 level of 102.4
the population mean is appropriate with a sample of
for participants with impaired glucose tolerance. An
n independent sampling units and when the charac-
investigator wishes to test whether the mean is higher
teristic under study is approximately normally distrib-
than 102.4 in patients who have had Type 2 diabetes
uted. If the sample size is large (e.g., n > 30), then the
for 10 years or more.
distributional assumption can be relaxed. If the sam-
The tests for the mean and proportion are outlined in
ple size is small and the distribution of the outcome
Table 3. It is important to note that these tests can be
is highly nonnormal, then a nonparametric test (which
criticized, however, because the comparator (i.e., µ0, π0)
does not assume normality), such as the Wilcoxon
is often based on historical data and might not represent
signed rank test, should be used (Rosner, 1995). The
an appropriate comparison. Comparisons are often more
formula for the confidence interval for the population
appropriate when the comparison groups are evaluated
proportion is appropriate as long as the sample has
in parallel or concurrently (see below).
at least five independent sampling units in each of the
Two-Sample Procedures for Means
When the primary outcome is continuous and there
Table 3. Tests of Hypothesis for the Population are two independent comparison groups (e.g., patients
Mean and the Population Proportion assigned to an active drug or placebo, normal versus
Test for Population Test for Population overweight patients), then a confidence interval for the
Mean µ0a Proportion π0b difference in means can be produced or a test for a dif-
Null hypothesis µ = µ0 π = π0 ference in means can be performed. The appropriate
use of the two-independent sample t test assumes that
Research hypothesis µ ≠ µ0 π ≠ π0
there are independent sampling units in each of two
Test statistic x p̂ independent comparison groups, that the outcome is
t z 0

s/ n 0 (1 0 ) approximately normally distributed, and that the vari-


n ances in the groups are comparable. Again, if the sam-
a
Where x is the mean in the study sample, µ0 is the mean ple sizes are large, then the normality is a non-issue.
specified under the null hypothesis, s is the standard devia- Equality of variances (or lack thereof) can be reconciled
tion in the study sample, and n is the sample size. in the procedure with the use of appropriate formulas
s (D’Agostino et al., 2004). If the sample sizes are small
is the standard error (or variability of the sample mean).
n and the data are non-normal, then a nonparametric test
b
where p̂ is the proportion in the study sample, π0 is the such as the Wilcoxon rank sum test should be used
proportion specified under the null hypothesis, and n is the (Rosner, 1995). The confidence interval for the differ-
sample size.
ence in means is given in Table 4.

©2008 Elsevier Inc. All rights reserved.  53


Techniques

Table 4. Confidence Interval and Test of Hypothesis for the Difference in Means
CI for difference in population meansa 1 1
( x1 x 2 ) t sp
n1 n2
Test for difference in independent population means µ1 − µ2
Null hypothesis µ1 = µ2
Research hypothesis µ1 ≠ µ2
Test statistica x1 - x 2
t
sp 1 1
n1 n2
a
Where x1 and x2 are the means in the study samples, t is the value from the t distribution reflecting the desired confidence level
(e.g., 95%), sp is the pooled standard deviation (appropriate when the population variances are assumed to be equal and computed
2 2
(n 1 1)s 1 (n 2 1)s2
by combining the variances in the two study samples, sp ), and n1 and n2 are the respective sample sizes.
n1 n 2 2

Using the data summarized in Figure 4, a 95% con- When the data are matched or paired, then the analy-
fidence interval for the difference in mean RBP4 levels sis is focused on difference scores. For example, sup-
between normal and overweight participants is 28.2 ± 14.1, pose a study is conducted in which measures of serum
or (14.1, 42.3). The difference in means is 28.2 units with a RBP4 are taken on n sampling units at baseline and then
margin of error of 14.1 units. We are 95% confident that the again after 6 weeks of exposure to an exercise program.
true difference in mean RBP4 levels between normal and Suppose the objective is to assess the change in the
overweight participants is between 14.1 and 42.3 units. primary outcome in response to the exercise program.
Comparing mean RBP4 levels between normal and Because two measurements are taken on each sam-
overweight using a test of hypothesis (see Table 4) pro- pling unit, we violate the assumption of independence of
duces t = −4.92, which is highly statistically significant with sampling units. The procedure is to compute difference
p = 0.0027 (i.e., the mean RBP4 levels are statistically sig- scores on each unit by subtracting the measurements
nificantly different between participants who are of normal (e.g., baseline to 6 weeks). A confidence interval for the
weight as compared to overweight). The confidence inter- mean difference or a test about the mean difference in
val and test of hypothesis are two different approaches the population can be conducted. The confidence inter-
to making the comparison. The 95% confidence interval val formula and the hypothesis testing procedure are
provides the range of plausible values for the difference shown in Table 5.
in means (i.e., 14.1–42.3), whereas the test of hypothesis It is very important to note that in the paired test (and
produces the significance of the difference (i.e., p value = confidence interval for paired data), summary statistics
0.0027). Because the confidence interval does not include (i.e., the mean and standard deviation) are based on dif-
0 (i.e., the null value), the confidence interval also indicates ference scores.
that there is a significant difference in means. Tests for Means in More Than Two Groups
When there are more than two independent groups, the
procedure to test for differences in means is analysis
Table 5. Confidence Interval and Test of Hypothesis
of variance (ANOVA). In ANOVA, there are k (>2) inde-
for the Mean Difference in Matched or Paired
pendent groups and again variances among groups are
Samples
assumed to be equal. In addition, data are assumed to
CI for population mean differencea sd
xd t follow a normal distribution. The procedure for testing
n the equality of means is shown in Table 6.
Test for population mean difference µd The above is suitable to test for differences in means
Null hypothesis µd = 0 across groups defined by a single factor (e.g., treatments
or exposures). For example, using the data summarized
Research hypothesis µd ≠ 0
in Figure 4, we can compare the mean serum RBP4 lev-
Test statistica els by obesity status using ANOVA. The test produces
t=
F = 19.6, which is highly statistically significant with p =
0.0014 (i.e., the three means are significantly different).
a
Where xd is the mean of the difference scores in the study
sample, md is the mean difference specified under the null ANOVA is a very general procedure that can also be
hypothesis, t is the value from the t distribution reflecting the used to test for differences in means as a function of
desired confidence level, sd is the standard deviation of the two or more factors. For example, suppose we wish to
difference scores in the study sample, and n is the sample test for differences in expression in various cell types
size (i.e., the number of independent sampling units, equal to exposed to different experimental conditions. Two-fac-
the number of pairs).
tor ANOVA is used to test for differences in expression

54  ©2008 Elsevier Inc. All rights reserved.


Techniques

Table 6. Test of Hypothesis for Difference in k


explicit control of the overall level of significance across
Independent Population Means
a set of hypothesis tests. Popular multiple comparison
tests include the Tukey and Fisher’s least significant
Null hypothesis µ1 = µ2 = µ3 = . . . = µk
difference procedures. When designs include a single
Research hypothesis Means not all equal control group and multiple experimental groups and
Test statistica
nj (X j X ) 2 /(k 1) it is of interest to compare each experimental group
F
(X X j ) 2 /(N k) to the control, Dunnett’s procedure is appropriate. It
should be noted that regardless of the specific proce-
a
Where Xj is the mean of the jth study sample, X is the overall
dure used, only tests that are of clinical interest should
mean (computed by pooling study samples), nj is the sample
size in the jth group, k is the number of groups, and N is the be performed as opposed to all possible tests.
total sample size (pooling all study samples). Tests for Proportions in Two or More Groups
When there are two or more independent groups and the
outcome is dichotomous (or discrete with more than two
due to cell type, due to experimental condition, and due categories), the procedure to test for differences in pro-
to the interaction between the two. For more details on portions is the chi-square test. The data are organized
ANOVA, and higher-order ANOVA in particular, see Ros- into a two-way table, with the outcome variable and the
ner (1995) and Cobb (1998). grouping variable as the rows and columns of the table,
Another popular application of ANOVA involves taking respectively. The numbers of sampling units in each cat-
repeated assessments on the same sampling units over egory of the response within each group are summed.
time. For example, a study may involve n = 5 participants, The procedure for testing the equality of proportions is
each of whom is measured monthly over a period of 6 shown in Table 7.
months. There are not n = 30 independent sampling units, The procedure in Table 7 is suitable to test for differ-
but rather five independent units measured six times each. ences in proportions across comparison groups, such
The appropriate analysis must account for repeated assess- as to test for differences in the proportions of patients
ments on the same units and is called repeated-measures with diabetes across groups defined by obesity status.
ANOVA. For more details, see Littell et al. (1998). The procedure is appropriate when there are a sufficient
In ANOVA, we test for a difference in k independent number of sampling units in each cell of the table. When
means. If the test is significant, we conclude that the there are fewer sampling units, exact procedures are
means are not all equal. Investigators are often inter- required (Agresti, 2002).
ested in which means are different. A series of pairwise
tests (i.e., comparing means two at a time) can then Sample Size Considerations
be performed to assess specific differences. Each pair- The precision and power of statistical procedures depend
wise test can be performed using the test for a differ- on the sample size or the number of sampling units avail-
ence in independent means described above. However, able for analysis. In general, the larger the sample size,
because there is a positive probability of incorrectly the better. Studies should not be too small, because they
rejecting the null hypothesis in each test (specifically, will not be able to answer the study question posed. On
the level of significance, often selected at 0.05), over a the other hand, studies should not be too large, because
series of tests this probability of incorrectly rejecting at resources can be wasted. Studies that are too small or
least one of the tests can inflate to an unacceptably high too large can be viewed as unethical.
level. When it is of interest to perform pairwise tests (or Investigators should perform sample size computa-
other general contrasts), following the rejection of the tions prior to mounting studies to determine the appro-
null hypothesis in an ANOVA, a multiple comparison priate sample size needed. When studies fail to demon-
procedure should be used to control the overall level of strate statistical significance (i.e., fail to reject the null
significance. There are a number of these procedures hypothesis), it may be the case that there is no effect of
that vary according to the number and nature of the the treatment or it may be that the study was too small to
desired comparisons. A key feature of all tests is their demonstrate a difference.

Table 7. Test of Hypothesis for Difference in Summary


Independent Proportions The appropriate statistical analysis depends on the
research question of interest, the nature of the outcome
Null hypothesis Proportions are all equal
variable (e.g., continuous or discrete), the number of
Research hypothesis Proportions are not all equal comparison groups, and the specific study design (e.g.,
Test statistica 2 (O E) 2 independent, sometimes called parallel-group designs,
E or dependent or repeated-measures designs). This
a
Where O represents the observed frequency in each cell of paper is meant to organize the procedures according
the two-way table and E represents the expected frequency to these criteria. There are, however, many details that
in each cell of the two-way table (under the assumption that require further consideration in the application and inter-
the null hypothesis is true).
pretation of these procedures.

©2008 Elsevier Inc. All rights reserved.  55


Techniques
References Anim. Sci. 76, 1216–1231.

Rosner, B. (1995). Fundamentals of Biostatistics (Belmont, CA:


Agresti, A. (2002). Categorical Data Analysis, Second Edition (New
Duxbury Brooks/Cole).
York: John Wiley & Sons).
Sullivan, L.M. (2006). Statistical primer for cardiovascular research:
Cobb, G. (1998). Introduction to Design and Analysis of Experi-
estimation from samples. Circulation 114, 445–449.
ments (New York: Springer Verlag).

D’Agostino, R.B., Sullivan, L.M., and Beiser, A. (2004). Introductory Please cite this article as:
Applied Biostatistics (Belmont, CA: Duxbury Brooks/Cole). Dukes, K.A., and Sullivan, L.M. (2007). A Review of Basic Biosta-
tistics. In Evaluating Techniques in Biochemical Research, D. Zuk,
Littell, R.C., Henry, P.R., and Ammerman, C.B. (1998). Statisti- ed. (Cambridge, MA: Cell Press), http://www.cellpress.com/misc/
cal analysis of repeated measures data using SAS procedures. J. page?page=ETBR.

56  ©2008 Elsevier Inc. All rights reserved.

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