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Desain Cossover
Desain Cossover
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Outline
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Introduction to design of crossover trials
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crossover longitudinal study
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tistically efficient and require fewer subjects than
do non-crossover designs, even other repeated mea-
sures designs.
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Introduction to design of crossover trials, cont’d
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Table 3: 3-period, 2-treatment crossover designs (AAB|ABA|BAA)
Period 1 Period 2 Period 3
Sequence AAB A A B
Sequence ABA A B A
Sequence BAA B A A
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Introduction to design of crossover trials, cont’d
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Introduction to design of crossover trials, cont’d
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Introduction to design of crossover trials, cont’d
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over effects, but the development can be generalized
if higher-order carryover effects need to be consid-
ered.
I Uniformity
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Introduction to design of crossover trials, cont’d
I Latin Squares
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4! = 24 possible sequences from which to choose, the
Latin square only requires 4 sequences.
I Balanced Designs
Table 10: 4-sequence, 4-period, 2-treatment crossover design: a strongly balanced and
uniform design
Period 1 Period 2 Period 3 Period 4
Sequence ABBA A B B A
Sequence BAAB B A A B
Sequence AABB A A B B
Sequence BBAA B B A A
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Introduction to design of crossover trials, cont’d
I Statistical Bias
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♠ The expectations of these estimators:
1 1
E (µ̂A) = (µA + v + p + µA − v − p + λB ) = µA + λB
2 2
1 1
E (µ̂B ) = (µB + v − p + λA + µB − v + p) = µB + λA
2 2
1
E (µ̂A − µ̂B ) = µA − µB − (λA − λB ) (13)
2
• From (13) the direct treatment effects and the
treatment difference are not aliased with sequence
or period effects, but are aliased with the carry-
over effects.
• The treatment difference is not aliased with car-
ryover effects when the carryover effects are equal,
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i.e., λA = λB .
• The results in (13) are due to the fact that the
AB|BA crossover design is uniform and balanced
w.r.t. first-order carryover effects.
Any crossover design, which is uniform and bal-
anced w.r.t. first-order carryover effects, such as
the designs in Tables 5 and 8, also exhibits these
results.
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Table 12:
Period 1 Period 2 Period 3
Sequence ABB µA + v + p1 µB + v + p2 + λA µB + v − p1 − p2 + λB
Sequence BAA µB − v + p1 µA − v + p2 + λB µA − v − p1 − p2 + λA
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♠ The expectations of these estimators
1
E (µ̂A) = (µA + v + p1 + µA − v + p2 + λB + µA − v − p1 − p2 + λA)
3
1
= µA + (λA + λB − v)
3
1
E (µ̂B ) = (µB + v + p2 + λA + µB + v − p1 − p2 + λB + µB − v + p1)
3
1
= µB + (λA + λB + v)
3
2
E (µ̂A − µ̂B ) = µA − µB − v (16)
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• From (16), the direct treatment effects are aliased
with the sequence effect and the carryover effects.
• The treatment difference only is aliased with the
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sequence effect.
• The results in (16) are due to the ABB|BAA
crossover design being uniform within periods
and strongly balanced w.r.t. first-order carryover
effects.
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Introduction to design of crossover trials, cont’d
E (µ̂A)
1
= (µA + v + p1 + µA − v + p2 + λB + µA − v − p1 − p2 + λA + λ2B )
3
1
=µA + (λA + λB + λ2B − v)
3
E (µ̂B )
1
= (µB + v + p2 + λA + µB + v − p1 − p2 + λB + λ2A + µB − v + p1)
3
1
=µB + (λA + λB + λ2A + v)
3
1 2
E (µ̂A − µ̂B ) = µA − µB − (λ2A − λ2B ) − v (18)
3 3
• From (18) the treatment mean difference is aliased
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with second-order carryover effects.
I Complex Carryover
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period in which treatment A is administered
λBB : the carryover effect of treatment B into a
period in which treatment B is administered
This will certainly complicate things!
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Introduction to design of crossover trials, cont’d
I Implementation Overview
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a role. Once this determination is made, then an ap-
propriate crossover design should be employed that
avoids aliasing of those nuisance effects with treat-
ment effects. This is a decision that the researchers
should be prepared to address.
♠ Example:
• An investigator wants to conduct a two-period
crossover design, but is concerned that he will
have unequal carryover effects so he is reluctant
to invoke the 2 × 2 crossover design.
• If the investigator is not as concerned about se-
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quence effects, Balaam’s design in Table 8 may
be appropriate.
• Balaam’s design is uniform within periods but
not within sequences, and it is strongly balanced.
Therefore, Balaam’s design will not be adversely
affected in the presence of unequal carryover ef-
fects.
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♠ Obviously, randomization is very important if the
crossover design is not uniform within sequences
because the underlying assumption is that the se-
quence effect is negligible.
♠ Randomization is important in crossover trials even
if the design is uniform within sequences because
biases could result from investigators assigning pa-
tients to treatment sequences.
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♠ increased patient comfort in later periods with trial
processes;
♠ increased patient knowledge in later periods;
♠ improvement in skill and technique of those re-
searchers taking the measurements.
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♣ A list of various crossover designs with some, all, or
none of the properties
Uniform Uniform
within within Strongly
Sequences Periods Balanced Balanced Examples
no no no no AAB|ABB, ABCC|BCAA
yes no no no ABB|BAB, ABC|CBA
no yes no no ABCC|BCAA|CABB
no no yes no ABAA|BAAB
no no yes yes AABBA|BAABB
yes yes no no ABC|BCA|CAB
yes no yes no AABA|ABAA
no yes yes no ABA|BAB
yes no yes yes AABBA|ABBAA
no yes yes yes ABB|BAA, AB|BA|AA|BB
yes yes yes no AB|BA
yes yes yes yes ABBA|BAAB|AABB|BBAA
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Introduction to design of crossover trials, cont’d
I Statistical Precision
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• Within-patient variability tends to be smaller than
between-patient variability.
♠ The variance components are as follows:
• WAA: between-patient variance for treatment A
• WBB : between-patient variance for treatment B
• WAB : between-patient covariance between treat-
ments A and B
• σAA: within-patient variance for treatment A
• σBB : within-patient variance for treatment B
♠ Expressions for the variance of the estimated treat-
ment mean difference for each of the two-period,
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two-treatment designs:
Table 14:
Design Variance
Crossover σ /n = {1.0(WAA + WBB ) − 2.0WAB + (σAA + σBB )} /n
2
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α significance level test with 100(1 − β)% power and
effect size µA − µB is
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♠ Assume
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• Another issue in selecting a design is whether
the experimenter wishes to compare the within-
patient variances σAA and σBB .
• For the 2 × 2 crossover design, the within-patient
variances can be estimated by imposing restric-
tions on the between-patient variances and co-
variances.
• The estimators of σAA and σBB , however, may
lack precision and be unstable. Hence, the 2 × 2
crossover design is not recommended when com-
paring σAA and σBB is an objective.
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• The parallel design provides optimal estimation
of the within-unit variances because it has 12 n pa-
tients who can provide data in estimating each
of σAA and σBB , whereas Balaam’s design has 41 n
patients who can provide data in estimating each
of σAA and σBB .
• Balaam’s design is a compromise between the 2×
2 crossover design and the parallel design.
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Statistical analysis of crossover trial data
I Continuous Outcome
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♠ In sequence AB, the Period 1 vs. Period 2 differ-
ence expectation
µAB = µB + v − p + λA − (µA + v + p) = µA − µB + 2p − λ.
µBA = µA − v − p + λB − (µB − v + p) = µB − µA + 2p − λ.
H0 : µAB − µBA = 0 ⇐⇒ H0 : µA − µB = 0
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• Two-sample t test
• Wilcoxon rank-sum test (Mann-Whitney-Wilcoxon
rank-sum test)
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hours after treatment
• One-day washout period between treatment pe-
riods
• The estimated treatment mean difference was 46.6
L/min in favor of formoterol (p = 0.0012) and the
95% confidence interval for the treatment mean
difference is (22.9, 70.3).
• The Wilcoxon rank-sum test also indicated statis-
tical significance between the treatment groups
(p = 0.0276).
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Statistical analysis of crossover trial data, cont’d
I Binary Outcome
H0 : p1· − p·1 = 0
⇐⇒H0 : p1· − p·1 = (p10 + p11) − (p01 + p11) = p10 − p01 = 0,
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data instead of the probabilities listed above.
Failure (0) on B Success (1) on B
Failure (0) on A n00 n01
Success (1) on A n10 n11
♠ McNemar’s test
• Given the number of patients who displayed a
treatment preference, n10+n01, n10 follows a binomial(n10+
n01, p) distribution and the null hypothesis re-
duces to testing
H0 : p = 0.5
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of patients that would be successful with either
treatment in support of the null hypothesis, look-
ing at only the cells where there was success with
one treatment and failure with the other.
• The data in cells for both success or failure with
both treatments would be ignored.
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♠ 22 patients displayed a treatment preference, of
which 7 preferred A and 15 preferred B.
♠ McNemar’s test indicated that this was not statis-
tically significant (exact p = 0.1338).
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• The probability of a 50-50 split between treat-
ments A and B preferences under the null hy-
pothesis is equivalent to the odds ratio (OR) for
the treatment A preference to the treatment B
preference being 1.0.
• Because logistic regression analysis models the
natural logarithm of the odds, testing whether
there is a 50-50 split between treatments A and
B preferences is comparable to testing whether
the intercept term is null in a logistic regression
analysis.
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• To account for the possible period effect in the
2 × 2 crossover trial, a term for period can be
included in the logistic regression analysis.
♠ Example: Use the same data set partitioned as to
patients within the two sequences
Sequence AB Failure (0) on B Success (1) on B
Failure (0) on A 10 7
Success (1) on A 3 5
I Time-to-Event Outcome
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that on B, the patient is assigned a (0,1) score and
prefers B.
♠ If the time to treatment failure on B is less than
that on A, the patient is assigned a (1,0) score and
prefers A.
♠ If the patient does not experience treatment failure
on either treatment, the patient is assigned a (1,1)
score and displays no preference.
♠ Hence, we can use the procedures which we imple-
mented with binary outcomes.
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Statistical analysis of crossover trial data, cont’d
♠ Continuous Outcome
• A mixed-effects linear model (e.g., SAS PROC
MIXED) to account for the repeated measure-
ments that yield period, sequence, and carryover
effects and to model the various sources of intra-
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patient and inter-patient variability
♠ Binary Outcome
• Generalized estimating equations (GEE) (e.g., SAS
PROC GENMOD) to account for the repeated
measurements that yield period, sequence, and
carryover effects and to model the various sources
of intra-patient and inter-patient variability
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Power analysis for crossover trials
♠ P (reject H0|H0) = α
• H0: null hypothesis; Ha: alternative hypothesis
♠ Type I error: concluding that a treatment effect or
difference exists when, in reality, it does not
♠ a false positive
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2. Power = 1- probability of type II error (=1 − β =
0.8 or 0.9)
♠ P (accept H0|Ha) = β
♠ Type II error: concluding that a treatment effect
or difference does not exist when, in reality, it does.
• a false negative
♠ Power = P (reject H0|Ha) = 1 − β : the chance of de-
tecting a specified (effect) size as being statistically
significant
♠ usually unknown
♠ needed to be estimated from either literature or
preliminary data collected from a pilot study
♠ If not available, e.g., for normally distributed data,
consider a standardized treatment effect (difference)
δ/σ while doing power analyses
5. Sample size (N )
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Power analysis for crossover trials, cont’d
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ation of PEF are about µA = 330 and σA = 40 for
Xilodol and µB = 310 and σB = 55 for Brantium,
and that each pair of measurements on the same
subject will have a correlation of about 0.3.
• The powers of both one-sided and two-sided paired
t-tests of mean difference, with a significance level
of α = 0.01, for a sample size of 100 patients are
0.865 and 0.801, respectively.
Note that the allocation ratio of patients to the
two sequences is irrelevant in this analysis.
• The choice of statistical test depends on which
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assumptions are reasonable.
One possibility is a t test.
• A paired or two-sample t test is valid when there
is no carryover effect and no interactions between
patients, treatments, and periods.
See, e.g., Senn (2002, Chapter 3)1 for more
details.
• The choice between a paired or a two-sample test
depends on what we assume about the period
effect.
If no period effect is assumed, a paired t test
1
Senn, S. Cross-over Trials in Clinical Research, 2nd ed. Chichester, England: John Wiley & Sons, 2002
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is the appropriate analysis for the design, with
the first member of each pair being the Xilodol
measurement (regardless of which sequence the
patient belongs to).
Otherwise, the two-sample t test approach is
called for because this analysis adjusts for the
period effect by using an extra degree of freedom.
• See Figure 1 for plot of power versus sample size
for paired t analysis of crossover design for a
range of 50 to 200 patients.
♠ Example: (Equivalence trial) A study establishing
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similarity between two new medications, “Xilodol”
and “Brantium”
• For example, the absolute mean PEF difference
is at most 35.
• Consider this goal if, e.g., one of the drugs has
fewer side effects and if a difference of no more
than 35 is considered clinically small.
• Instead of a standard t test, conduct an equiv-
alence test of the treatment mean difference for
the two drugs.
• Test the hypothesis that the true difference is less
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than -35 or more than 35
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rameter values in the above example, the power
of the paired equivalence test, with a significance
level of α = 0.01, for a sample size of 100 patients
is 0.598.
• See Figure 2 for plot of power versus sample size
for paired equivalence test for crossover design
for a range of 50 to 200 patients.
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Paired t Test for Mean Difference
1.0
0.9
0.8
Power
0.7
0.6
0.5
0.4
Figure 1: Plot of Power versus Sample Size for Paired t Analysis of Crossover Design for a Range of
50 to 200 Patients 85
Equivalence Test for Paired Mean Difference
1.0
0.9
0.8
0.7
Power
0.6
0.5
0.4
0.3
0.2
Figure 2: Plot of Power versus Sample Size for Paired Equivalence Test for Crossover Design for a
Range of 50 to 200 Patients 86
References
1. https://onlinecourses.science.psu.edu/stat509/node/123
• crossdes
• Crossover
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4. Schuirmann, D.J. (1987). A Comparison of the two one-
sided tests procedure and the power approach for assess-
ing the equivalence of average bioavailability, Journal of
Pharmacokinetics and Biopharmaceutics, 15, 657-680.
88