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Also by the same author: MEDSEQ, SSD, STTT and TABCHI

                 
          
 



GROUP SEQUENTIAL EXPERIMENT PLANS AD MODUM POCOCK: AN 
ADAPTATION FOR MEDICINE, WITH POWER TRIALS BY COMPUTER
SIMULATION.


       E H Lehmann  GP  Haugesund, Norway


                        #


SUMMARY

Experiment plans of the sequential type are attractive for
ethical and economical reasons.  A simple way to design
two-sample group sequential experiments of the type
advocated by Pocock is described. The procedure is based on
Student's t-test and Wilcoxon's two-sample rank test (using
t-test on ranks) and has been validated with regard to
realised power, level of significance and mean sample size
by computer simulation. The purpose of the present text is
to further more frequent use of sequential experiment plans
in medicine.

The effect of deviation from the study plan, in the form of
delayed testing, is discussed in Appendix 1.  Appendix 2
explains how, when planning the statistical tests,  more
than one hypothesis may be considered.

                         #

            In memoriam Knut Westlund.

                         #
  
                     (290507)

                
                      PREFACE

During the 1960s, the Faculty of Medicine in Bergen suffered
from lack of statisticians.  Having received my M.D. licence in
1965, and trying to do research, I had to act as my own
statistician, found statistics fascinating, and picked up as
much reading and formal education as circumstances permitted.

Rather soon, I found myself teaching medical statistics in
Bergen, Troms and Trondheim. In this period, it was necessary
to encourage the idea of being one's own statistician.  However,
my ambition was to be a clinical physician, and in 1983, I left
university life to start my general practice.

However, new attempts at research brought statistics to the
foreground again. The need to economize and to lessen the sum of
pain for patients as well as for research animals called for the
at that time relatively new type of experiment plan termed
'group sequential'. I wanted to present this design to fellow
physicians, in order to aid those still having to manage their
statistics alone, and also to facilitate cooperation with
statisticians.  Together with my colleague, dr Hogne Sandvik in
Bergen, I wrote a computer program for this purpose.

A brief presentation of group sequential plans, aimed at
clinicians, is given by Pocock in his textbook about clinical
trials.  However, the plan he recommends is prepeared for
bell-formed distributions, based as it is on the normal
distribution and Student's t-test. - In medical statistics, we
have to deal with all imaginable types of distribution. Hence,
for fixed sample experimentation, the rank test named after
Wilcoxon, Mann and Whitney (W-test) is a standard tool,
presented in every textbook of medical statistics.

How would group sequential experiments, performed with
non-normal distributions and using both those tests, stand with
regard to power and realised sample sizes?  To satisfy my
curiosity, I performed computer simulations, using constructed
example distributions.

Curiosity satisfied, then why issue the present work?  I am
convinced that group sequential experiment design should be used
more often, for ethical as well as economical reasons.  Perhaps
the present work can encourage colleagues that would like to try
this design. Hopefully, the present work will show that it is
easy to perform, can be used with safety with non-normal
distributions, and is more flexible and robust than often
thought and taught. - The text is largely non-mathematical, but
knowledge of elementary statistical concepts, of Student's 
t-test and of Wilcoxon's two-sample rank test is supposed.
Any textbook of statistics in medicine will render the
necessary background.

I want to thank my teachers, no one named, no one forgotten.  
Thanks are also due to my wife and best friend, Torunn Moksheim
Lehmann, dr. philos., for her patient support and assistance.

Haugesund, Norway, 2007 

Egil Henrik Lehmann, GP, Cand. med. (Bergen, Norway) . -
Postgraduate Certificate in  Applied Statistics (Sheffield
Hallam University, U.K.)
                                                             
                
                                                             

                              
                           Page 1
INTRODUCTION

Medicine cannot advance without experimenting with human beings
and research animals. This places an ethical burden on those
responsible: One should make determined efforts not to include
more individuals than strictly necessary, especially when the
procedures are risky or painful.

One way to diminish the number of participants is by so-called
sequential experiment plans. The basic idea is to terminate the
experiment as soon as a result which is statistically
significaant has been reached. By this method, results may be
attained using an average 30 to 40 per cent fewer individuals in
the long run, than necessary by ordinary fixed sample studies.
Even larger savings are possible in situations where there
is little advance information.

The history and basic information needed to plan group
sequential experiments in the two-sample situation has been
summarised by Pocock (1995) and references.  His tables were
derived from the normal distribution with known standard
deviation (SD). However, as Armitage puts it: '..We have assumed
so far that the observations are normally distributed with known
variance. This is, of course, unlikely to be true, but...the
normal distribution methodology often provides a useful
approximation for a wide range of other situations' (Armitage,
2002, p 621).

- The first statistician to apply Student's t-test to group
sequential plans was Armitage. Use of the two-sample rank test
named after Wilcoxon, Mann and Whitney ('W-test') for this
purpose was suggested by Pocock. Those interested in the early
history of sequential tests may consult Whitehead (1997, p 16),
who also in his book summarises the basic mathematical theory. A
valuable survey has been given by Armitage (1991).

The adaptation described below is based on well-known methods.
I want to present a procedure than may be used when data are
gaussian ('normal') as well as non-normal, and to show that the
procedure is safe in practice. The method can be used by an
experimenter who must plan his/her study without the assistance
of a statistician. Even if such assistance is available, being
able to present a preliminary plan may improve communication and
cooperation.

In general, sequential plans may be classified as group
sequential plans (Repeated test plans, RST) versus fully
sequential plans.  In RST plans, the individuals (animals or
persons) are brought into the experiment a certain number (a
'group') at a time, and the total amount of data collected up to
this point subjected to a statistical test.  If the result turns
out to be statistically significant, the study is ended.  If
not, the next group is brought in. - However, it goes (almost)
without saying that an experiment can be terminated at any time
when necessary for ethical or other compelling reasons.  'No
single stopping rule can take account of all these features'
(Armitage 2002, p 623).


                           Page 2

A maximal number of individuals that can be entered must be
stipulated beforehand. If this number is reached, the study is
to be terminated regardless of result.  How to calculate this
maximal sample size will be shown below.

Since the RST design constitutes an extension of methods already
well known by experimenters, namely the t-test and the W-test,
it is not demanding with regard to theory and analysis.

RST plans may be subdivided according to spacing of statistical
tests and levels of significance used. The simplest type is a
two-sample plan where samples are kept equally large.  Likewise,
groups are (as far as possible) kept equally large, and
statistical tests are performed at a constant nominal level of
significance (Pnom). This is the type of plan advocated by
Pocock (1977, and 1995 pp 147-155).

The pros and cons of sequential plans will not be discussed
here.  Suffice it to say that such plans are useful only in
studies where the timespan for treatment and observation of an
individual is short, compared to total study time. 

                                                          
LIMITATIONS. TERMINOLOGY. 

The present text is limited to the simple two-sample type of
experiment, to continuous (measurement) data, and to Student's
t-test and Wilcoxon's two sample rank test (below, the
'W-test'). For practical reasons, the W-test is performed as a
t-test of ranks, which is known to give results very close
to the original method, except for non-normal, very small
samples.

A 'group' contains an equal number of individuals for each of
the two samples. The test performed when data from one group has
been joined with the data previously collected has been termed a
'look'. All the tests planned, except for the last one, are
called 'interim' tests. The actual number of tests for a given
experiment (a realisation) is unknown a priori, since the
experiment is to be terminated if one of the interim tests leads
to the verdict of statistical significance. The maximal number
of tests is equal to the maximal number of groups.

When an experiment (fixed sample or sequential) is planned, the
first step is always to formally define the main hypotesis to be
investigated, commonly designated H1.  Thereafter, a decision
must be made regarding the wanted power and level of
significance of the statistical test.  A brief reminder: Power
is the probability of CORRECTLY concluding 'significance'. Level
of significance is the risk of INCORRECTLY concluding
'significance'.

To decide sample and study size, a calculation which takes
targeted power and level of significance (LOS) into account is
indispensable. Table 1 and Table 2 show the results of such
calculations, so that a user need not be burdened with them.

Sample size also depends on the expected difference, under H1,
between the two samples with regard to mean values.  This
difference is conventionally expressed in standard deviation
units, and is then called  'standardised difference' and
sometimes  'shift' or (in clinical settings) 'reference
improvement'.

For this, consider the range of possible shifts which is
expected to emerge from the experiment. Standard advice is to
proceed with the smallest shift that is of practical importance
or possible to investigate. (See Appendix 2 for more details).

                           Page 3 
      
Nominal P values for t-test based group sequential plans of the
Pocock type are reproduced in Table 3 below. Armed with tables
1, 2 and 3, it should be possible for an experimenter with the
statistical training given in medical school to plan group
sequential experiments ad modum Pocock.

However, users need to be certain that this procedure is
reliable with regard to realised (attained) power and realised
level of significance. 

To find out how far this ideal can be achieved, I have carried
out validation experiments by computer simulation, drawing data
at random from example distributions.  The resulting tables are
numbered 4 to 7 and have been labelled according to distribution
and wanted power and wanted total level of significance (Ptot).
                                                              

MORE ABOUT DETERMINATION OF MAXIMAL SAMPLE SIZES

When planning fixed sample experiments, we select sample sizes
that fulfil our power demands. When it comes to sequential
plans, the whole idea is that sample size is a variable that
takes a value dictated by the results. Still, we must feel
confident that targeted power and LOS is reached.

We see that there must be put an upper limit on total sample
size, or else one would run the risk of having to continue the
experiment forever. Our task is then to stipulate this upper
limit (maximal sample size) at a level that takes care of power.
Consequently, we need to establish maximal sample sizes for
conventionally desired total power levels of 80, 90 and 95 per
cent, and wanted total LOS or 'Ptot' (one- and two-sided tests)
of 5 per cent (0.05).

These sample sizes can be calculated from the sample sizes for
ordinary fixed group experiments. Recommended sample sizes for
two-group fixed sample experiments are shown by Table 1.  All we
need to do is to increase the sample size found in Table 1 by a
certain percentage taken from Table 2. Table 2 was established
by the present author by simulations, i.e. trial and error.

The ordinary method of calculating sample sizes for ordinary
fixed sample experiments is based on the so-called 'standardised
difference', or 'shift' (Above, also referred to as 'reference
improvement') The shift may be described as the hypothetical a
priori stipulated difference between population mean values that
the experiment should reveal, divided on a hypothetical a priori
assessed distribution standard deviation, 'SD'.

Consequently, at this point, if the distribution SD is poorly
known, it must be estimated.  If experience indicates an
expected sample range, a reasonable thumb rule is to assume
distribution SD equal to 1/4 of the sample range. If the
distribution must be expected to be rectangular or U-shaped, the
SD should then be set equal to 1/3 of the range.



                           Page 4

Sample size calculations are sensitive to assumed
distribution SD.  If the latter is set too low, the calculated
sample size will be too small, which may ruin the experiment.
Hence, if the SD estimates at hand are vague, a high (though
realistic) estimate should be used.  This may in some cases lead
to larger maximal sample sizes than necessary.  However, maximal
sample sizes that turn out to be larger than necessary are not a
problem in group sequential experimentation.  In fact, the very
purpose of sequential plans is to let the data determine the
sample size finally realised. 

Table 1 shows sample sizes for fixed size experiments.  The
ordinary method of calculating sample sizes is texbook material
(see e.g. Armitage 2002, pp 137-146).  By simulation trials, I
found that in general, adding three units to sample sizes
calculated by the ordinary method produce sample sizes which
take care of power in small-sample non-normal experiments.  This
'adjustment' has been used in Table 1.

Table 2 shows percentage units to add to sample sizes for fixed
sample experiments in order to establish sample sizes for group
sequential experiments. The author compiled Table 2 by
simulation trials, i.e., by systematic trial and error. The
table is supposed to establish maximal sample sizes ensuring
sufficient power regardless of the distribution of the data.


NOMINAL LEVELS OF SIGNIFICANCE

When planning a group sequential experiment, a series of
statistical tests (t-tests or W-tests) is envisaged. To achieve
the wanted total LOS (Ptot), each test must be performed on a
nominal level of significance (Pnom) which is stricter than
wanted total LOS (Ptot).  Moreover, Pnom must be set to a value
which ensures that total, realised LOS (realised Ptot) is close
to the target value, usually 0.05.

Column three in Table 3 shows recommended nominal levels of
significance for group sequential tests (Pnom), as tabulated by
McPherson (1974). In the fourth column are given Pnom values for
Ptot 0.025 (one sided), equivalent to 0.05 (two sided).

A two-sided test is just two one-sided tests combined into a
single calculation, each performed with half of the wanted LOS.

Whether to use one-sided or two-sided tests sometimes lead to
unnecessary discussion. The answer is completely dependent on
the hypothesis being tested. Using a two-sided test when
investigating a one-sided hypothesis is wasteful, and thus
in conflict with the basic idea of sequential plans.

                           Page 5

A SUMMARY OF THE PROCEDURE

Planning a group sequential experiment ad modum Pocock may then
be summarised in eight steps:

1) Stipulate null hypothesis (H0) and alternative hypothesis
(H1), in terms of standardised difference.

2) Stipulate target characteristics: Wanted power and Ptot.

3) Stipulate maximal number of groups (the same as maximal
number of tests, or 'looks').
                                                                  
4) Find in Table 1 the sample size needed for a fixed sample
experiment with the required shift, LOS and power.

5) Calculate maximal sample size by adding relevant percentage
of units indicated by Table 2. (It is easy to forget that study
size is usually two times sample size.)

6) Calculate group size by integer division of maximal sample
size by number of groups. The remainder of the division is
included with the last group of the plan. 

7) Find from Table 3, Pnom.

8) Select test: Student's two-sample t-test or Wilcoxon's
two-sample test (t-test on ranks). Using both tests, as control
of each other, is a good idea.

The experiment plan is now ready, as far as statistical design
is concerned.  However, in practice, this sequence must often be
repeated until a satisfactory design is reached. 

Of course, there is much more to study design than the
statistical part, but that need not concern us here.

For an example, envisage a situation where we want to verify the
existence of a standardised difference  at least as large as 0.5
SD units.  In statistical terms, we want to test the null
hypothesis (H0) 'standardised difference is zero' against the
alternative hypothesis (H1) 'standardised difference is 0.5 or
more'. In case H1 should be true, we want the chance of
revealing this by our tests (power) to be at least 0.9.

In case the true standardised difference should not be 0.5, but
rather zero, we want the risk of a falsely significant result (P
value) to be at most 0.05. (At present, the possibility of a
negative standardised difference or a standardised difference
taking a value between zero and 0.5 or higher is ignored.)

A one-sided test is indicated here, since we have a one-sided
hypothesis. If it were just as possible that the standardised
difference could take the value minus 0.5 as plus 0.5, we would
have needed a two sided test.


                           Page 6

Table 1 shows that a fixed sample experiment for this purpose
should have a sample size of 72 and hence a total study size of
144.

Let number of looks be e.g. five. Table 2 shows that a suitable
maximal sample size can be found by increasing 72 with 28 per
cent, which leads to a maximal sample size of 92. Maximal total
study size is then 184.

However, if H1 should be true, the study will most likely be
terminated long before maximum sample size is reached.  The
realised study size might turn out to be in the region of 100 -
110 individuals.  This compares favourably with the study size
of a similar fixed sample experiment, which would be 72 x 2, or
144. - 

Now, if H0 should be true, the total number of individuals, 184,
might be included before termination. In this case the group
sequential design would be uneconomical in comparison with the
fixed group design. However, there are ways to avoid the latter
situation, see Appendix 2.

Since 92 divided by 5 is not an integer, we cannot space the
looks so that all groups have exactly the same size.  However,
if groups are set to 18 (per sample) and the last group to 20,
we have a satisfactory distribution of looks.

                    

VALIDATION STUDY: STOCHASTIC SIMULATIONS

The purpose of the present validation study is to verify by
computer simulation that group sequential plans, constructed
according to the above principles, work well in practice.  That
is, with realistic simulated data they produce results that
reach or pass the targets with respect to realised total power
and realised total LOS. They should also lead to a marked
reduction (on the average) of number of individuals involved, in
comparison with fixed sample experiments.

The data (the observations) are supposed to emerge from empiric
example distributions, constructed from experience to represent
distribution types frequently encountered in practice.

In addition to assuming  H1: Shift = 0.5, we shall also test a
plan assuming H1: Shift = 1.0 -  Moreover, in addition to aiming
at a total LOS of 0.05, we shall study the result of aiming at a
total LOS of 0.025. Our power requirement (the chance we want to
have of revealing the alternative hypothesis if it is true) will
be the conventional 0.8, 0.9, or 0.95 (80, 90 or 95 per cent).


                           Page 7

EXAMPLE DISTRIBUTIONS

The following empirical frequency distributions were used for the
stochastic simulations.

Class limits were 1,2,...M with M up to 14.  Thus, there were M-1
intervals, the lower limit of the lowest interval was 1 and the upper
limit of the highest interval was M.  The number of intervals was
kept low in order to save computer time. This implies approximation,
but experience showed that using as few as 6 to 8 class intervals
did not lead to critical errors in the present context.

Below, interval numbers are given in the form (n), and
frequencies as proportions. The statistics of the distributions
were calculated from the frequencies. The traditional
measurements of skewness was calculated from 3rd moment and
kurtosis (peakedness) from 4th moment using textbook formulas
(Hartung 1995, pp 47-49).


Example A - Bell-shaped (truncated normal) distribution.
(1):.00298 (2):.00934 (3):.02784 (4):.06559 (5):.12098 (6):.17566
(7):.19742 (8):.17566 (9):.12098 (10):.06559 (11):.02784 (12):.00934
(13):.00298
Range: 13   Mean: 7.52   SD: 1.02  Skewness: 0.00  Kurtosis: 2.92

Example B - Unimodal, positive skew.
(1):.05 (2):.55 (3):.21 (4):.11 (5):.05 (6):.02 (7):.01
Range: 7   Mean: 3.16   SD: 1.13  Skewness: 2.06  Kurtosis: 5.08

Example C - Rectangular (uniform).
(1):.1667 (2):.1667 (3):.1667 (4):.1667 (5):.1667 (6):.1667
Range: 6  Mean: 7.41  SD: 1.71   Skewness: 0.00  Kurtosis: 1.73 
 
Example D: J-shaped, positive skew.
(1):.5 (2):.25 (3):.1 (4):.07 (5):.04 (6):.03 (7):.01
Range: 7  Mean: 2.53  SD: 1.40   Skewness: 2.35  Kurtosis: 4.73

Example E: Peaked and long-tailed, symmetric.
(1):.01 (2):.01 (3):.01 (4):.02 (5):.05 (6):.15 (7):.5 (8):.15
(9):.05 (10):.02 (11):.01 (12):.01 (13):.01
Range: 13  Mean: 7.50  SD: 1.61  Skewness: 0.00  Kurtosis: 7.2

Example F: Low dome, symmetric.
(1):.11 (2):.14  (3):.16  (4):.18  (5):.16  (6):.14  (7):.11
Range: 7  Mean: 4.50   SD: 1.85  Skewness: 0.00  Kurtosis: 1.93

Example G: U-shaped, symmetric
(1):.25 (2):.15 (3):.1 (4):.1  (5):.15  (6):.25
Range: 6  Mean: 4.0  SD: 1.96  Skewness: 0.00  Kurtosis: 1.42

Example H: Bimodal, symmetric
(1):.02 (2):.03  (3):.05 (4):.3 (5):.04 (6):.04 (7):.04 (8):.04 (9):.04
(10):.3  (11):.05 (12):.03 (13):.02
Range: 13  Mean: 7.5  SD: 3.22  Skewness: 0.00  Kurtosis: 1.54

Example I: Dome-shaped with outliers
(1):.05 (2):.20 (3):.30 (4):.20 (5):.05 (6):.00 (7):.05  (8):.10 
(9):.05 
Range: 9  Mean: 4.5  SD: 2.21  Skewness: 0.99  Kurtosis:  2.85

                                                          Page 8

SIMULATION METHOD

The 'freeware' simulation programs SEQY and SEQZ were used
(Lehmann and Sandvik, 1995).  These programs simulate group
sequential plans of the present type, with data produced
by random sampling from two populations having congruent
frequency distributions, only separated by a difference in
location on the number line (shift).  The hypotheses tested is
of the same kind as in the fixed sample case: The null
hypothesis: Shift = zero.  Tables for H1: Shift = 0.5 or H1:
Shift = 1.0 has been produced.

The ordinary textbook version of the t-test was used, assuming
normal distributions with equal variances.  Wilcoxon's test was
performed in the form of a t-test on ranks, which is known to
render results very close to those obtained when using tables,
except on very small, non normal data.  This form of the W-test
was practical because calculation of the 'exact' probabilities is
not straightforward.

The simulation method used here may be classified technically as
a composition method, where a distribution is simulated as 
a compound of uniform distributions (Ripley 1987, p 63).

The reasons for using this composition method and a set of
empirical distributions instead of mathematically defined
distributions are the following: 1) A frequency distribution is
easier for most experimenters to understand and to compare with
actual data than a mathematically defined distribution. 2) Using
the composition method, any distribution type encountered in
practice can be simulated without being mathematically defined.

The simulations to be reported were performed on personal
computers using the operating system MS-DOS 5.  The
pseudo-random number generator of Microsoft Basic (Compiler
version 4.5) was used. The random number generator was re-seeded
for every experiment simulated, using the timer (clock) of
Microsoft Basic. The risk of repetition of random number
sequences is therefore supposed to be small.  Malfunction of the
random number generator was not noticed. Each simulation
statistic in the following is based on 10000 - ten thousand -
simulated experiments (replications).


VALIDATION TABLES

For all the validation simulations, the null hypothesis (H0) is
'Shift (delta) = 0.0'. The alternative hypotesis (H1) is 
'Shift = 0.5', alternatively 'Shift = 1.0', see table headings.

Power is proportion of experiments, supposing H1 is true,
terminated by a test concluding 'significant'. The 'beta error'
of statistical theory is equal to 1 minus power. Realised
significance is proportion of experiments, supposing H0 is true,
concluding 'significance'.  This is the 'alpha error' of
statistical theory.


                           Page 9

Rightmost column of the tables, 'Saving', shows difference
between mean realised sample size and sampe size needed for a
comparable fixed sample experiment. The difference is presented
as a percentage of the latter.


DESIGNATION OF TABLES

The validation tables are numbered 4,5,6 or 7. 
The tables are numbered with respect to H1 and target
total LOS, as shown below.
 
++++++++++++++++++++++++++++++++
Tables   Shift       Target
num-     according   total LOS
bered    to H1       (one sided)
--------------------------------
 4 -       0.5        0.05
 5 -       1.0        0.05
 6 -       0.5        0.025
 7 -       1.0        0.025
++++++++++++++++++++++++++++++++

The table number is followed by a letter showing the type of
distribution used, A to I, see list of distributions above.

The table designations end with the number 1 or 2, according to
statistical test used: Student's t-test 1, Wilcoxon's two-sample
test 2.

The tables show, from left to right: Number of looks (maximal
number of groups), nominal LOS (taken from Table 3), calculated
maximal sample sizes (using Tables 1 and 2), achieved power,
achieved sample sizes (median and mean), and achieved LOS (using
simulation under the null hypothesis. The rightmost column shows
'saving' of experimental individuals as a percentage, calculated
by subtracting realised mean sample size from sample size
necessary for fixed sample experimentation (from Table 1), with
the latter as divisor.


For example, Table 6C1 shows the results of assuming a shift of
0.5 SD units, a J-shaped distribution with right skew, and
using Student's t-test.


RESULTS (VALIDATI0N): REALISED POWER AND LOS

Inspecting the tables, we notice that when using the t-test, the
target values of realised power and LOS were comfortably reached
for the bell-shaped distribution (Example A). As expected, for
this distribution, the W-test was inferior with regard to power.

The t-test also performed well for the rectangular and the
dome-shaped distributions (Examples C and F) except that when
group sizes were small (number of looks high), there was a
tendency towards unconservative Ptot (values on the high side).
Here too, the W-test was inferior with regard to power. In
addition,  in some cases, for small groups, unconservative Ptot
results are seen.

Consequently, when working with rectangular or dome-shaped
distributions, the t-test should be preferred and group sizes
set to five or more (for each sample).


                           Page 10   

For skewed distributions (Examples B and D) the W-test was far
more powerful than the t-test while targeted Ptot was attained
reasonably well.  Also for the peaked, longtailed distribution,
this was the case (Example E). However, when using the W-test, 
when groups were small, again unconservative realised total 
LOS values were seen.

As a precaution, when working with skewed or with peaked,
longtailed distributions, the W-test is reliable, but group
sizes should be set to five or more.

The bimodal symmetric and the U-shaped symmetric distributions
(examples G and H) showed different properties, depending on the
magnitude of the shift. With shift = 0.5 SD, the W-test was more
powerful than the t-test, but when shift was 1.0, the inverse
was the case.  This difference seems large enough to demand
attention. - Further data, not given here, suggested that the
breakpoint, where the two tests are equally powerful, is situated
near the shift value of 0.75.

Therefore, when working with data having U-shaped or bimodal
distributions, shift must be taken into consideration when
selecting the best test of the two ones in question.

A tendency to unconservative Ptot could be seen in some cases
with the bimodal distribution, even when groups were not small.
The question whether unconservative Ptot values can be tolerated
must also be addressed, and if not, how to avoid or adjust for
this danger.

Dome-shaped distributions with outlying values often emerge in
medicine (example I). The W-test showed clearly better power as
well as better Ptot characteristics than the t-test in this case.


ABOUT MAXIMAL SAMPLE SIZES 

In some of the present trials, far higher power was attained
than originally planned (Examples B, D, E, with the W-test).

Hence, in hindsight, in the latter cases, maximal sample sizes
could have been markedly reduced without inappropriate loss of
power.  However, we notice that in those cases where maximal
sample sizes could have been reduced, the design led to
relatively early termination of the experiments, so that the
loss of economy stemming from unnecessary large maximal sample
sizes was compensated for, at least partly.

It has been stated that there is little to gain by increasing
the number of groups (looks, maximal number of tests) beyond
five (1).  This was verified by several of the present cases
(Examples A, C, F). However, in those cases where the maximal
sample size could have been reduced, a considerable decrease in
average sample size was seen when using a maximum of ten groups,
compared to using a maximum of five groups (Examples B, D, E).
Clearly, the largest 'saving' would be achieved using fully
sequential plans.

                           Page 11

SAVING IN TERMS OF SAMPLE SIZES

The main argument for using sequential methods is that in the
long run, they lead to a reduction of realised sample sizes.
Clearly, the apparent number 'saved' is influenced by the way
baseline fixed sample sizes are calculated.

The percentage saved, in terms of baseline fixed sample sizes,
are given in the rightmost columns of tables A to I.  These
savings are seen to range from 11 to 66 per cent, and were
larger when targeted power was high (.95 and .90) than when it
was low (.80).  However, note that these savings were achieved
only under H1, that is, when the standardised difference was
supposed to be 0.5 or 1.0. The savings achieved in the long run,
performing large numbers of real experiments, depend on the
results. If there is a large proportion of 'not significant'
results, the group sequential technique may lead to loss rather
than to savings. To avoid this unhappy consequence, small pilot
experiments and other type of a priori information seem
essential.

In the present paper, the baseline fixed sample sizes were
calculated by the standard texbook method, with the modification
of adding three units. The purpose of this 'adjustment' is to
conserve power when experiments are small. Without it, sample
size savings would perhaps have turned out a little lower.


FINAL REMARKS

From time to time, the opinion is voiced that for ethical and
economical reasons, sequential experiments should be used more
often.  That can hardly be expected to happen before these
methods have been popularised to a higher degree than today, and
have been made better known among clinical physicians and
experimenters.  The present text represents an attempt in this
direction.

Experimenters need not only to know that sequential methods
exist, but also, to 'see how they work'. Computer simulation can
demonstrate their strengths, weaknesses and oddities in an
unsurpassed manner.  Hopefully, the present text is convincing
in this respect. The MEDSEQ programs SEQY and SEQZ may be
downloaded free of charge (Lehmann and Sandvik 1995).

Attaining satisfactory power and LOS is the 'sine qua non' of
any study design. Thus, the present text has been concentrated
on these questions. Once power and LOS have been ascertained,
other problems may be faced.

Judging the attained power and LOS of the present simulations is
not made easier by the fact that there appears to be no general
rule for this.  Clearly, a certain variation around and/or
systematic deviation from target values could in many cases be
tolerated. Tentatively, realised power might be regarded as
satisfactory even if realised value turn out to be one or two
percentage units below target value.  Likewise, realised LOS
values (Ptot) might be regarded as satisfactory even if they
turn out to be one half to one percentage units above target
value.

It has been pointed out that the present Pocock-style plans are
rigid, and that exact group sizes may be difficult to attain in
practice.  'The effects of departure from the intended schedule
on the power function ... can be quite serious' (Whitehead 1997,
page 186). One may ask how critical this is, or whether modest
deviations from the plan can be tolerated.


                          Page 12

Simulation trials with five-group plans, reported in the
Appendix, indicate that one delay, leading to enlargement of one
of the groups with up to 1/2 of group size (with compensatory
reduction of the following group) does not very much influence
the result. Even larger delays does not at all ruin the
experiment. For further discussion please see the Appendix.

Many workers prefer confidence intervals to statistical tests.
Confidence intervals and statistical tests are two ways of
performing the same procedure. One of these methods does not
exclude the other. Supplementing the tests with confidence
intervals appear to be especially useful in cases where
premature termination is discussed.
 
For further practical and theoretical information, see the
article by Armitage (1991) and the relevant chapter in his
book (2002).


CONCLUSION

The outlined approach to planning group sequential experiments
ad modum Pocock has been shown to be safe and robust with regard
to P value (alpha error) as well as to Power (1 minus beta
error), regardless of distribution type.

The present trials demonstrated that in comparison with fixed sample
experimentation, in many cases a saving in terms of participants
of 50 per cent or more may be achieved.  Also, the design is
robust with regard to certain deviations for the plan.

It is the opinion of the author that group sequential design
ad modum Pocock can be realised by clinicians and other physicians.
This could lead to improvement with regard to time, economy and
ethics, in clinical research as well as in research using
laboratory animals.

                           XXXXX

                           Page 13
                         
                                                       
REFERENCES 

Armitage P. Sequential medical trials, 2nd edition.  Oxford:
Blackwell, 1975.

Armitage P. Interim analysis in clinical trials. Statistics
in medicine 1991; 10:925-937.

Armitage P, Berry G, Mattews JNS. Statistical Methods in Medical
Research.  Malden, Massachusetts, Blackwell Science, 2002.

Hartung J, Elpelt B, Klsener K-H. Statistik. Lehr- und
Handbuch der angewandten Statistik. Mnchen, R. Oldenbourg
Verlag, 1995.

Lehmann EH, Sandvik H. MEDSEQ - dataprogram for sekvensielle
forsk. Tidsskrift for Den norske lgeforening 1995; 115: 2304.

McPherson K. The problem of examining accumulated data more
than once. The New England Journal of Medicine 1974; 290: 501-502.

Pocock SG. Group sequential methods in the design and
analysis of clinical trials. Biometrika 1977; 64, 2: 191-199.

Pocock SJ. Clinical trials, a practical approach.
Chichester: John Wiley and Sons, 1995.

Ripley BD. Stochastic simulation. New York: John Wiley &
Sons, 1987.

Whitehead J. The Design and Analysis of Sequential Clinical
Trials. Revised Second Edition. Chichester, John Wiley & Sons,
1997.

                           XXXX

                      *** TABLES ***


Table 1 

SAMPLE SIZES NEEDED FOR FIXED SAMPLE EXPERIMENTS WITH 
STIPULATED STANDARDISED DIFFERENCE, LEVEL OF SIGNIFICANCE 
('LOS') AND POWER.  

Levels of significance: .05 and .025 (one sided tests).(*)

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
  Differ-         ----------------- Power ----------------
  ence,SD         0.8               0.9               0.95                
  units       .05    .025       .05     .025      .05     .025       
---------------------------------------------------------------
  0.1         1244   1581       1723    2115      2178    2616
  0.2          313    397        433     531       547     656       
  0.25         202    255        278     341       351     421
  0.3          141    178        194     238       245     293
  0.4           81    102        110     135       139     166
  0.5           53     66         72      87        90     108 
  0.6           37     47         51      62        63      76
  0.7           27     35         38      46        47      56
  0.75          25     31         34      41        42      49
  0.8           22     28         30      36        37      44
  0.9           18     22         24      29        30      35
  1             15     19         20      24        25      29
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

(*) Sample sizes for LOS .05 (two sided test) are the same as for 
LOS .025 (one sided test).



Table 2

GROUP SEQUENTIAL EXPERIMENT PLANS AD MODUM POCOCK: KEY 
PERCENTAGES FOR CALCULATING MAXIMAL SAMPLE SIZES.

Levels of significance: .05 and .025 (one sided tests).(*) 

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Wan-                       Group sequential plans        
ted                  -------------------------------------
power       LOS      Looks=2(**) Looks=3 Looks=5 Looks=10  
----------------------------------------------------------
0.80        0.05         16       23       31       42    
0.90        0.05         15       21       28       38    
0.95        0.05         14       20       25       35    
0.80        0.025        14       20       25       35    
0.90        0.025        13       19       23       32    
0.95        0.025        12       18       21       28    
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

(*) Sample sizes for LOS .05 (two sided test) are the same as for 
LOS .025 (one sided test).

(**) 'Looks' is maximal number of tests (interim tests plus
the eventual final test), here equal to maximal number of 
groups.



Table 3

TWO-SAMPLE, GROUP SEQUENTIAL EXPERIMENT EXPERIMENT PLANS AD
MODUM POCOCK: NOMINAL LEVELS OF SIGNIFICANCE (Pnom), SET EQUAL
FOR INTERIM* TESTS AND FINAL TEST, AIMING AT A REALISED TOTAL
LEVEL OF SIGNIFICANCE OF 0.05 (ONE SIDED OR TWO SIDED).  
After Klim McPherson (1974).

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
'Looks' Interim     One sided    Two sided                    
  **    tests       tests        tests                        
----------------------------------------------------------------
   1       0        0.0500       0.025   One group, i.e. fixed
   2       1        0.0296       0.0148    -\ sample experiments
   3       2        0.0221       0.01105   -|                  
   4       3        0.0183       0.00915   -|                  
   5       4        0.0159       0.00795   -|  Group           
   6       5        0.0142       0.0071     -- sequential      
   7       6        0.0130       0.0065    -|  experiments.    
   8       7        0.0120       0.0060    -|                  
   9       8        0.0113       0.00565   -|                  
   10      9        0.0107       0.00535   -/                  
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

*  The expression 'interim tests' is used for all tests on the 
plan except for the last one. 
** The term 'looks' is used for maximal number of test sessions,
interim tests plus final test, which is also the meximal number
of groups.












Table 4 - A - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK 

Distribution: Example A - Bell-shaped (truncated normal).
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
----------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1    .05       53      .808      53     53.0     .044        -
   2    .0296     61      .810      61     45.9     .038       13 
   3    .0221     65      .810      42     44.1     .040       17
   5    .0159     69      .811      39     43.3     .040       18
  10    .0107     75      .810      42     43.7     .041       18

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1    .05       72      .900      72     72.0     .043        -
   2    .0296     83      .908      41     57.1     .040       21
   3    .0221     87      .906      58     52.9     .039       27
   5    .0159     92      .900      54     50.3     .036       30
  10    .0107     99      .905      45     49.2     .040       32

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1    .05       90      .954      90     90.0     .043        -
   2    .0296    103      .957      51     65.9     .037       27
   3    .0221    108      .956      36     59.3     .037       34
   5    .0159    113      .951      44     55.0     .034       39
  10    .0107    122      .958      48     53.0     .038       41
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 4 - A - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK 

Distribution: Example A - Bell-shaped (truncated normal).
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
----------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .782     53     53.0      .040        -
   2     .0296     61     .787     61     46.2      .038       13
   3     .0221     65     .787     42     45.0      .035       15
   5     .0159     69     .789     39     44.0      .042       17
  10     .0107     75     .793     42     44.1      .042       17

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .891     72     72.0      .040        -
   2     .0296     83     .889     41     58.1      .038       19
   3     .0221     87     .888     58     54.2      .040       25
   5     .0159     92     .883     54     51.7      .040       28
  10     .0107     99     .884     45     50.8      .042       29

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1      .05      90     .939     90     90.0      .040        -
   2      .0296   103     .947     51     67.8      .035       25
   3      .0221   108     .950     72     61.0      .035       32
   5      .0159   113     .939     44     56.6      .035       37
  10      .0107   122     .942     48     55.1      .039       39
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++





Table 4 - B - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example B - Unimodal, positive skew.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05      53      .797     53     53.0      .048        -
   2     .0296    61      .804     61     45.8      .045       14
   3     .0221    65      .810     42     44.1      .043       17
   5     .0159    69      .803     39     43.0      .045       19
  10     .0107    75      .815     42     42.8      .047       19

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05      72      .897     72     72.0      .049        -
   2     .0296    83      .907     41     57.1      .049       21
   3     .0221    87      .905     58     52.8      .045       27
   5     .0159    92      .910     54     49.8      .049       31 
  10     .0107    99      .915     45     47.7      .046       34

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05      90      .950     90     90.0      .051        -
   2     .0296   103      .954     51     66.2      .046       26
   3     .0221   108      .957     36     59.4      .045       34
   5     .0159   113      .949     44     55.1      .046       39
  10     .0107   122      .956     48     52.0      .045       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - B - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example B - Unimodal, positive skew.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .939     53     53.0      .047        -
   2     .0296     61     .943     30     39.6      .046       25
   3     .0221     65     .951     42     36.0      .043       32
   5     .0159     69     .950     26     33.3      .045       37
  10     .0107     75     .955     28     31.6      .048       40

    Target: Power >= .9, Ptot <= .05 one sided (<= .1 two sided)  

   1     .05       72     .981     72     72.0      .047        -
   2     .0296     83     .984     41     48.6      .046       33
   3     .0221     87     .985     29     42.1      .044       42
   5     .0159     92     .987     36     37.5      .047       48
  10     .0107     99     .988     27     34.5      .050       52

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .994     90     90.0      .048        -
   2     .0296    103     .995     51     56.3      .049       37
   3     .0221    108     .995     36     47.0      .047       48
   5     .0159    113     .995     44     40.3      .048       51
  10     .0107    122     .996     36     36.3      .047       60
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++





Table 4 - C - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution:  Example C - Rectangular (uniform)
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .813     53     53.0      .051        -
   2     .0296     61     .818     61     45.8      .051       14
   3     .0221     65     .815     42     44.2      .050       17
   5     .0159     69     .809     39     43.2      .052       18
  10     .0107     75     .818     42     43.5      .045       18

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .904     72     72.0      .050        -
   2     .0296     83     .909     41     56.9      .051       21
   3     .0221     87     .912     58     52.6      .048       27
   5     .0159     92     .908     54     50.1      .050       30
  10     .0107     99     .905     45     49.0      .050       32

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .954     90     90.0      .052        -
   2     .0296    103     .956     51     65.2      .051       28
   3     .0221    108     .957     36     58.9      .047       36
   5     .0159    113     .954     44     53.8      .049       40
  10     .0107    122     .959     48     52.2      .047       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 4 - C - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution:  Example C - Rectangular (uniform).
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .772     53     53.0      .047        -
   2     .0296     61     .786     61     46.6      .047       12
   3     .0221     65     .782     42     45.2      .053       15
   5     .0159     69     .776     39     44.7      .050       16
  10     .0107     75     .782     42     45.3      .054       15

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .877     72     72.0      .052        -
   2     .0296     83     .881     41     58.2      .051       19
   3     .0221     87     .878     58     54.6      .051       24
   5     .0159     92     .875     54     52.4      .049       27
  10     .0107     99     .885     45     50.9      .055       29

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .929     90     90.0      .051        -
   2     .0296    103     .937     51     67.3      .047       25
   3     .0221    108     .940     72     61.2      .046       32
   5     .0159    113     .936     44     56.9      .045       37
  10     .0107    122     .935     48     55.8      .045       38
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - D - 1 

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example D - J-shaped, positive skew.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .811     53     53.0      .049        -
   2     .0296     61     .924     30     45.4      .050       14
   3     .0221     65     .812     42     44.0      .042       17
   5     .0159     69     .815     39     42.6      .048       20
  10     .0107     75     .826     42     42.3      .046       20

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .907     72     72.0      .047        -
   2     .0296     83     .911     41     57.2      .045       21
   3     .0221     87     .906     58     52.6      .050       27
   5     .0159     92     .911     54     49.8      .046       31
  10     .0107     99     .911     46     47.5      .041       34

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .954     90     90.0      .047        -
   2     .0296    103     .955     51     65.8      .044       27
   3     .0221    108     .953     36     58.9      .045       35
   5     .0159    113     .958     44     53.6      .045       40
  10     .0107    122     .960     48     51.8      .044       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 



Table 4 - D - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example D - J-shaped, positive skew.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .964     53     53.0      .050        -
   2     .0296     61     .970     30     37.3      .049       30
   3     .0221     65     .973     21     33.1      .047       38
   5     .0159     69     .971     26     30.2      .047       43
  10     .0107     75     .978     21     28.0      .048       47

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .994     72     72.0      .047        -
   2     .0296     83     .993     41     46.3      .048       36
   3     .0221     87     .994     29     39.0      .044       46
   5     .0159     92     .994     36     33.7      .045       53
  10     .0107     99     .995     27     30.4      .047       58

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .998     90     90.0      .045        -
   2     .0296    103     .998     51     54.5      .045       36
   3     .0221    108     .998     36     43.7      .046       46
   5     .0159    113     .998     22     36.4      .044       60
  10     .0107    122     .999     24     32.5      .048       64
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 






Table 4 - E - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example E - Peaked and long-tailed, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .818     53     53.0      .048        -
   2     .0296     61     .819     61     45.6      .047       14
   3     .0221     65     .827     42     43.3      .045       18
   5     .0159     69     .814     39     41.7      .045       21
  10     .0107     75     .822     35     41.3      .040       22

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .904     72     72.0      .048        -
   2     .0296     83     .909     41     56.9      .046       21
   3     .0221     87     .910     58     51.8      .043       28
   5     .0159     92     .914     36     48.4      .040       33
  10     .0107     99     .916     36     46.3      .040       36

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .952     90     90.0      .046        -
   2     .0296    103     .954     51     65.5      .043       27
   3     .0221    108     .953     36     58.7      .042       35
   5     .0159    113     .955     44     52.9      .045       41
  10     .0107    122     .956     48     50.8      .040       44
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 



Table 4 - E - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example E - Peaked and long-tailed, symmetric.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .973     53     53.0     .048         -
   2     .0296     61     .982     30     36.3     .048        32
   3     .0221     65     .983     21     31.3     .047        41
   5     .0159     69     .986     26     28.4     .051        46
  10     .0107     75     .985     21     26.1     .050        51

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .994     72     72.0     .056         -
   2     .0296     83     .995     41     44.9     .050        38
   3     .0221     87     .996     29     37.2     .046        48
   5     .0159     92     .997     36     31.9     .043        56
  10     .0107     99     .998     27     28.2     .045        61

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .999     90     90.0     .048         -
   2     .0296    103     .999     51     53.3     .047        41
   3     .0221    108     .999     36     41.9     .046        53
   5     .0159    113     .999     22     34.5     .049        62
  10     .0107    122    1.000     24     30.3     .043        66
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 





Table 4 - F - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example F - Low dome, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .805     53     53.0      .049        -
   2     .0296     61     .809     61     45.7      .051       14
   3     .0221     65     .812     42     44.1      .044       17
   5     .0159     69     .799     39     43.3      .050       18
  10     .0107     75     .808     42     44.1      .050       17 

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .898     72     72.0      .050        -
   2     .0296     83     .908     41     57.2      .049       21
   3     .0221     87     .904     58     52.5      .049       27
   5     .0159     92     .908     54     50.1      .051       30
  10     .0107     99     .905     45     49.0      .048       32

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .944     90     90.0      .058        -
   2     .0296    103     .953     51     65.6      .052       27
   3     .0221    108     .951     36     59.7      .049       34
   5     .0159    113     .950     44     54.8      .052       39
  10     .0107    122     .952     48     53.4      .047       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - F - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example F - Low dome, symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .754     53     53.0      .051        -
   2     .0296     61     .765     61     47.0      .048       11
   3     .0221     65     .755     42     46.0      .051       13
   5     .0159     69     .755     52     45.4      .053       14
  10     .0107     75     .768     42     45.8      .050       14

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .861     72     72.0      .051        -
   2     .0296     83     .868     41     59.2      .049       18
   3     .0221     87     .865     58     55.7      .050       23
   5     .0159     92     .858     54     53.5      .049       26
  10     .0107     99     .863     45     52.7      .048       27

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .921     90     90.0      .053        -
   2     .0296    103     .926     51     68.6      .047       24
   3     .0221    108     .922     72     63.2      .052       30
   5     .0159    113     .922     44     58.6      .050       35
  10     .0107    122     .936     48     56.6      .049       37
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - G - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example G  U-shaped, symmetric
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .812     53     53.0      .048        -
   2     .0296     61     .817     61     46.0      .053       13
   3     .0221     65     .811     42     44.5      .053       16
   5     .0159     69     .811     39     43.0      .051       19
  10     .0107     75     .814     42     44.1      .055       17

     Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .903     72     72.0      .048        -
   2     .0296     83     .909     41     57.1      .051       21
   3     .0221     87     .910     58     52.8      .049       27
   5     .0159     92     .907     54     50.0      .045       31
  10     .0107     99     .910     45     49.4      .053       31

     Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .950     90     90.0      .052        -
   2     .0296    103     .956     51     66.0      .049       27
   3     .0221    108     .958     36     59.1      .045       34
   5     .0159    113     .954     44     54.5      .049       39
  10     .0107    122     .961     48     52.4      .049       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - G - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK

Distribution: Example G  U-shaped, symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .855     53     53.0      .050        -
   2     .0296     61     .874     30     43.4      .048       18
   3     .0221     65     .870     42     40.9      .052       23
   5     .0159     69     .868     39     39.8      .048       25
  10     .0107     75     .872     35     39.5      .049       25

     Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       72     .934     72     72.0      .053        -
   2     .0296     83     .939     41     53.8      .049       25
   3     .0221     87     .943     58     49.0      .051       32
   5     .0159     92     .944     36     45.8      .050       36
  10     .0107     99     .950     36     43.1      .053       40

     Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .972     90     90.0      .047        -
   2     .0296    103     .977     51     62.4      .052       31
   3     .0221    108     .977     36     54.6      .048       39
   5     .0159    113     .978     44     49.5      .049       45
  10     .0107    122     .980     36     46.7      .049       48
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - H - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .821     53     53.0      .057        -
   2     .0296     61     .830     30     45.2      .051       15  
   3     .0221     65     .834     42     43.4      .055       18
   5     .0159     69     .829     39     42.1      .062       21      
  10     .0107     75     .832     42     43.2      .058       18

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided) 

   1     .05       72     .917     72     72.0      .065        -
   2     .0296     83     .923     41     56.5      .061       22
   3     .0221     87     .925     58     51.7      .053       28
   5     .0159     92     .921     54     49.4      .054       31
  10     .0107     99     .920     45     47.7      .060       34

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .962     90     90.0      .055        -
   2     .0296    103     .967     51     64.5      .055       28
   3     .0221    108     .966     36     58.0      .056       36
   5     .0159    113     .964     44     53.3      .055       41
  10     .0107    122     .965     48     51.5      .054       43
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 4 - H - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .911     53     53.0      .061        -
   2     .0296     61     .926     30     41.0      .059       23
   3     .0221     65     .928     42     37.2      .058       30
   5     .0159     69     .926     26     35.0      .065       34
  10     .0107     75     .937     28     33.7      .064       36

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided) 

   1     .05       72     .974     72     72.0      .060        -
   2     .0296     83     .978     41     50.1      .058       30
   3     .0221     87     .977     29     43.9      .058       39
   5     .0159     92     .978     36     39.4      .055       45
  10     .0107     99     .982     36     37.0      .062       49

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       90     .992     90     90.0      .054        -
   2     .0296    103     .994     51     58.5      .061       35
   3     .0221    108     .993     36     49.0      .059       46
   5     .0159    113     .995     44     42.3      .059       53
  10     .0107    122     .994     36     38.7      .059       57
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 4 - I - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .810     53     53.0      .058        -
   2     .0296     61     .815     30     45.4      .057       14
   3     .0221     65     .818     42     43.6      .055       18
   5     .0159     69     .816     39     42.2      .059       20
  10     .0107     75     .818     42     42.6      .053       20

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided) 

   1     .05       72     .906     72     72.0      .057        -
   2     .0296     83     .906     41     57.1      .055       21
   3     .0221     87     .909     58     52.2      .059       27
   5     .0159     92     .912     36     49.8      .058       31
  10     .0107     99     .907     45     48.1      .060       33

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided)

   1     .05       90     .956     90     90.0      .059        -
   2     .0296    103     .977     61     73.5      .060       18
   3     .0221    108     .955     36     58.7      .060       35
   5     .0159    113     .952     44     54.4      .057       40
  10     .0107    122     .954     48     52.1      .053       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 4 - I - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       53     .960     53     53.0      .052        -
   2     .0296     61     .964     30     38.1      .049       28
   3     .0221     65     .970     21     33.7      .051       36
   5     .0159     69     .969     26     31.0      .052       42
  10     .0107     75     .972     28     29.0      .055       45

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided) 

   1     .05       72     .991     72     72.0      .054        -
   2     .0296     83     .993     41     46.6      .049       35
   3     .0221     87     .994     29     40.1      .049       44
   5     .0159     92     .995     36     34.9      .055       52
  10     .0107     99     .997     27     31.4      .052       56

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided)

   1     .05       90     .998     90     90.0      .052        -
   2     .0296    103     .999     51     55.0      .055       39
   3     .0221    108     .998     36     44.8      .052       50
   5     .0159    113     .998     22     37.7      .049       61
  10     .0107    122     .999     24     33.4      .054       63
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 5 - A - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example A - Bell-shaped (truncated normal) 
Test: Student's t-test (one sided)
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------

    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .839     15     15.0      .044        -
   2     .0296     17     .835     17     12.7      .047       15
   3     .0221     18     .840     12     12.2      .042       19
   5     .0159     20     .854     12     12.3      .042       18
  10     .0107     21     .842     12     12.3      .047       18
 
    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .927     20     20.0      .045        -
   2     .0296     23     .933     11     15.5      .049       23
   3     .0221     24     .929     16     14.4      .041       28
   5     .0159     26     .934     15     13.9      .043       31
  10     .0107     28     .928     12     13.9      .044       31

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 
 
   1     .05       25     .969     25     25.0      .040        -
   2     .0296     29     .974     14     18.0      .044       28
   3     .0221     30     .969     10     16.1      .042       34
   5     .0159     31     .970     12     14.7      .041       41
  10     .0107     34     .970     12     14.3      .043       43
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 5 - A - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example A - Bell-shaped (truncated normal) 
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .808     15     15.0      .041        -
   2     .0296     17     .817     17     12.7      .045       15
   3     .0221     18     .809     12     12.6      .042       16
   5     .0159     20     .832     12     12.0      .053       20
  10     .0107     21     .821     12     12.4      .042       17
 
    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .907     20     20.0      .043        -
   2     .0296     23     .920     11     15.5      .044       23
   3     .0221     24     .914     16     14.6      .045       27
   5     .0159     26     .921     15     14.1      .047       30
  10     .0107     28     .922     12     13.9      .046       31

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 
 
   1     .05       25     .950     25     25.0      .040        -
   2     .0296     29     .958     14     18.2      .046       27
   3     .0221     30     .961     20     16.6      .042       34
   5     .0159     31     .959     12     14.9      .048       40
  10     .0107     34     .966     12     13.1      .079       48
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 5 - B - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example B - Unimodal, positive skew
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .823     15     15.0      .049        -
   2     .0296     17     .830      8     12.4      .048       17
   3     .0221     18     .835     12     11.9      .043       21
   5     .0159     20     .850     12     11.8      .045       21
  10     .0107     21     .845     10     11.6      .046       23

     Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .914     20     20.0      .049        -
   2     .0296     23     .924     11     15.4      .047       23
   3     .0221     24     .915     16     14.2      .046       29
   5     .0159     26     .926     10     13.3      .043       34
  10     .0107     28     .924     10     13.1      .048       35

     Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .957     25     25.0      .048        -
   2     .0296     29     .963     14     18.2      .048       27
   3     .0221     30     .964     10     16.0      .049       36
   5     .0159     31     .960     12     14.4      .045       42
  10     .0107     34     .965     12     13.6      .045       46
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 



Table 5 - B - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example B - Unimodal, positive skew
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
     Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .897     15     15.0      .046        -
   2     .0296     17     .902      8     11.6      .057       23
   3     .0221     18     .906     12     11.3      .045       25
   5     .0159     20     .905      8     10.2      .061       32
  10     .0107     21     .916     10     10.5      .048       30

     Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .959     20     20.0      .051        -
   2     .0296     23     .965     11     14.2      .051       29
   3     .0221     24     .966      8     12.7      .050       37
   5     .0159     26     .974     10     11.9      .048       41
  10     .0107     28     .971      8     11.3      .051       43

     Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .985     25     25.0      .048        -
   2     .0296     29     .988     14     16.6      .050       34
   3     .0221     30     .987     10     14.5      .047       42
   5     .0159     31     .988     12     12.4      .050       50
  10     .0107     34     .990      9     10.3      .081       59
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 5 - C - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution:  Example C - Rectangular (uniform)
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .849     15     15.0      .049        -
   2     .0296     17     .844     17     12.8      .055       15
   3     .0221     18     .837     12     12.4      .052       17
   5     .0159     20     .847     12     12.6      .054       16
   10    .0107     21     .842     12     12.5      .059       17

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .925     20     20.0      .051        -
   2     .0296     23     .929     11     15.6      .052       22
   3     .0221     24     .925     16     14.6      .054       27
   5     .0159     26     .930     15     14.2      .054       29 
   10    .0107     28     .930     12     14.2      .069       29

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .969     25     25.0      .051        -
   2     .0296     29     .973     14     17.9      .045       28
   3     .0221     30     .970     10     16.3      .049       35
   5     .0159     31     .970     12     15.0      .055       40
   10    .0107     34     .969     12     14.6      .057       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 5 - C - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution:  Example 4 - Rectangular
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .783     15     15.0      .045        -
   2     .0296     17     .777     17     13.0      .052       13
   3     .0221     18     .774     12     12.9      .047       14
   5     .0159     20     .797     12     12.7      .059       15
   10    .0107     21     .797     12     13.0      .051       13

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .884     20     20.0      .050        -
   2     .0296     23     .889     11     16.0      .046       20
   3     .0221     24     .890     16     15.0      .053       25
   5     .0159     26     .890     15     14.9      .050       25
   10    .0107     28     .882     12     15.2      .048       24

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .940     25     25.0      .050        -
   2     .0296     29     .944     14     18.8      .052       25
   3     .0221     30     .940     20     17.4      .050       30
   5     .0159     31     .937     12     15.8      .058       37
   10    .0107     34     .946     12     14.2      .091       43
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 5 - D - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example D - J-shaped right skew
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .829     15     15.0      .048        -
   2     .0296     17     .841      8     12.5      .048       17
   3     .0221     18     .849     12     11.7      .044       22
   5     .0159     20     .858     12     11.6      .045       23
  10     .0107     21     .859     10     11.2      .044       25

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .919     20     20.0      .049        -
   2     .0296     23     .929     11     15.3      .049       23
   3     .0221     24     .925     16     14.0      .044       30
   5     .0159     26     .933     10     13.0      .042       35
  10     .0107     28     .931     10     12.6      .044       37

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 
 
   1     .05       25     .963     25     25.0      .049        -
   2     .0296     29     .965     14     17.9      .048       28
   3     .0221     30     .966     10     15.9      .046       36
   5     .0159     31     .963     12     14.2      .046       43
  10     .0107     34     .969     12     13.3      .044       47
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 


Table 5 - D - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example D - J-shaped right skew
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD


+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .920     15     15.0      .044        -
   2     .0296     17     .925      8     11.2      .048       25
   3     .0221     18     .928     12     10.8      .049       28
   5     .0159     20     .941      8      9.7      .065       35
  10     .0107     21     .942      8      9.8      .050       35

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .972     20     20.0      .053        -
   2     .0296     23     .974     11     13.7      .053       32
   3     .0221     24     .978      8     12.2      .050       39
   5     .0159     26     .980     10     11.2      .050       44 
   10    .0107     28     .983      8     10.5      .051       47

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 
 
   1     .05       25     .990     25     25.0      .050        -
   2     .0296     29     .994     14     16.1      .053       36
   3     .0221     30     .993     10     13.7      .048       45
   5     .0159     31     .993     12     11.8      .054       53
   10    .0107     34     .995      9      9.4      .085       62

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 


Table 5 - E - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example E - Peaked and long-tailed, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .842     15     15.0      .051        -
   2     .0296     17     .851      8     12.0      .043       20
   3     .0221     18     .856     12     11.3      .035       25
   5     .0159     20     .870      8     11.0      .035       27
  10     .0107     21     .872      8     10.6      .037       29

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .913     20     20.0      .051        -
   2     .0296     23     .925     11     15.2      .046       24
   3     .0221     24     .928      8     13.6      .039       32
   5     .0159     26     .935     10     12.5      .040       38
  10     .0107     28     .936      8     11.9      .035       41

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .956     25     25.0      .054        -
   2     .0296     29     .967     14     17.8      .044       29
   3     .0221     30     .964     10     15.6      .042       38
   5     .0159     31     .963     12     13.7      .038       45
  10     .0107     34     .967      9     12.6      .037       50
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 



Table 5 - E - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example E - Peaked and longtailed, symmetric.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .946     15     15.0      .047        -
   2     .0296     17     .952      8     10.9      .047       27
   3     .0221     18     .950     12     10.4      .042       31
   5     .0159     20     .963      8      8.9      .057       41
   10    .0107     21     .962      8      9.1      .041       39

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .985     20     20.0      .050        -
   2     .0296     23     .988     11     13.1      .049       35 
   3     .0221     24     .986      8     11.5      .048       43
   5     .0159     26     .989     10     10.4      .049       48
   10    .0107     28     .990      8      9.5      .052       53

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .995     25     25.0      .053        -
   2     .0296     29     .997     14     15.6      .047       38
   3     .0221     30     .996     10     13.2      .044       47
   5     .0159     31     .996     12     10.9      .049       56
   10    .0107     34     .998      6      8.5      .082       66
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 
 



Table 5 - F - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example F - Low dome, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05      15      .836     15     15.0      .049        -
   2     .0296    17      .838     17     12.8      .055       15
   3     .0221    18      .830     12     12.5      .052       17
   5     .0159    20      .844     12     12.6      .050       16
   10    .0107    21      .830     12     12.6      .056       16

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05      20      .919     20     20.0      .048        -
   2     .0296    23      .928     11     15.6      .049       22
   3     .0221    24      .921     16     14.6      .051       27
   5     .0159    26      .929     15     14.1      .050       29
   10    .0107    28      .921     12     14.3      .064       29

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05      25      .964     25     25.0      .052        -
   2     .0296    29      .971     14     18.1      .053       28
   3     .0221    30      .970     10     16.3      .053       35
   5     .0159    31      .965     12     15.2      .054       39
   10    .0107    34      .967     12     14.8      .053       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 5 - F - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example F - Low dome, symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delcta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .784     15     15.0      .050        -
   2     .0296     17     .776     17     13.0      .054       13
   3     .0221     18     .773     12     12.9      .046       14
   5     .0159     20     .803     12     12.5      .058       17
   10    .0107     21     .790     12     13.0      .050       13

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .879     20     20.0      .054        -
   2     .0296     23     .894     11     16.0      .049       20
   3     .0221     24     .881     16     15.1      .050       25
   5     .0159     26     .893     15     14.8      .051       26
   10    .0107     28     .886     12     15.0      .053       25

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .931     25     25.0      .052        -
   2     .0296     29     .948     14     18.7      .045       25
   3     .0221     30     .942     20     17.3      .050       31
   5     .0159     31     .941     12     15.6      .056       38
   10    .0107     34     .945     12     14.3      .083       43
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
  



Table 5 - G - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example G - U-shaped symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .838     15     15.0      .052        -
   2     .0296     17     .835     17     12.9      .052       14
   3     .0221     18     .833     12     12.6      .051       16
   5     .0159     20     .856     12     12.6      .055       16
   10    .0107     21     .841     12     12.4      .066       17

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .929     20     20.0      .047        -
   2     .0296     23     .931     11     15.6      .053       22
   3     .0221     24     .923     16     14.7      .045       27
   5     .0159     26     .931     15     14.2      .056       29
   10    .0107     28     .925     12     14.3      .069       29

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .968     25     25.0      .050        -
   2     .0296     29     .974     14     18.0      .048       28
   3     .0221     30     .972     10     16.2      .051       35
   5     .0159     31     .966     12     15.2      .054       39
   10    .0107     34     .969     12     14.7      .056       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++




Table 5 - G - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example G - U-shaped symmetric.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .785     15     15.0      .044        -
   2     .0296     17     .793     17     12.9      .052       14
   3     .0221     18     .783     12     12.9      .048       14
   5     .0159     20     .814     12     12.4      .060       17
   10    .0107     21     .800     12     12.9      .049       14

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .897     20     20.0      .049        -
   2     .0296     23     .896     11     15.8      .050       21
   3     .0221     24     .893     16     14.7      .051       27
   5     .0159     26     .896     15     14.7      .049       27
   10    .0107     28     .893     12     14.8      .053       26

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .941     25     25.0      .052        -
   2     .0296     29     .947     14     18.6      .052       26
   3     .0221     30     .946     20     17.0      .047       32
   5     .0159     31     .941     12     15.5      .053       38
   10    .0107     34     .948     12     14.2      .082       43
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++




Table 5 - H - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
--------------------------------------------------------------------- 
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .851     15     15.0      .048        -
   2     .0296     17     .845     17     12.8      .050       15
   3     .0221     18     .844     12     12.4      .051       17
   5     .0159     20     .851     12     12.6      .052       16
  10     .0107     21     .844     12     12.3      .069       18

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .930     20     20.0      .050        -
   2     .0296     23     .930     11     15.6      .049       22
   3     .0221     24     .927     16     14.6      .051       27
   5     .0159     26     .935     15     14.1      .051       29
  10     .0107     28     .935     12     13.9      .076       31

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .967     25     25.0      .047        -
   2     .0296     29     .974     14     18.0      .049       28
   3     .0221     30     .971     10     16.3      .049       35
   5     .0159     31     .967     12     15.2      .051       39
  10     .0107     34     .968     12     14.6      .057       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 


Table 5 - H - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .782     15     15.0      .046        -
   2     .0296     17     .782     17     13.0      .048       13
   3     .0221     18     .781     12     12.8      .048       15
   5     .0159     20     .802     12     12.5      .062       17
  10     .0107     21     .792     12     12.9      .045       14

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .884     20     20.0      .050        -
   2     .0296     23     .891     11     15.9      .050       21
   3     .0221     24     .894     16     14.8      .047       26
   5     .0159     26     .893     15     14.8      .047       26
  10     .0107     28     .891     12     14.6      .052       27

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .938     25     25.0      .051        -
   2     .0296     29     .950     14     18.6      .051       26
   3     .0221     30     .940     20     17.1      .050       32
   5     .0159     31     .940     12     15.7      .054       21
  10     .0107     34     .949     12     14.0      .083       44
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 5 - I - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .847     15     15.0      .051        -
   2     .0296     17     .849     17     12.6      .053       16
   3     .0221     18     .838     12     12.1      .045       19
   5     .0159     20     .860     12     11.9      .047       21
  10     .0107     21     .853     10     11.7      .051       22

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)

   1     .05       20     .924     20     20.0      .056        -
   2     .0296     23     .929     11     15.4      .051       23
   3     .0221     24     .925     16     14.3      .047       29
   5     .0159     26     .935     10     13.3      .051       33
  10     .0107     28     .933     19     13.0      .057       35

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .965     25     25.0      .052        -
   2     .0296     29     .969     14     17.9      .048       28
   3     .0221     30     .968     10     16.1      .048       36
   5     .0159     31     .965     12     14.5      .048       42
  10     .0107     34     .970     12     13.7      .047       45
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 


Table 5 - I - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .05 one sided (.1 two sided)   

   1     .05       15     .907     15     15.0      .047        -
   2     .0296     17     .909      8     11.4      .056       24
   3     .0221     18     .919     12     11.0      .049       27
   5     .0159     20     .935      8      9.9      .065       34
   10    .0107     21     .926      8     10.1      .051       33

    Target: Power >= .9, Ptot <= .05 one sided (.1 two sided)
 
   1     .05       20     .961     20     20.0      .053        -
   2     .0296     23     .970     11     13.9      .050       31
   3     .0221     24     .969      8     12.5      .056       37
   5     .0159     26     .975     10     11.6      .051       42
   10    .0107     28     .975      8     10.9      .050       45

    Target: Power >= .95, Ptot <= .05 one sided (.1 two sided) 

   1     .05       25     .986     25     25.0      .050        -
   2     .0296     29     .990     14     16.4      .052       34
   3     .0221     30     .990     10     14.2      .049       43
   5     .0159     31     .989     12     12.1      .052       52
   10    .0107     34     .993      9      9.8      .082       61
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 

Table 6 - A - 1  

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example A - Bell-shaped (truncated normal).  
Test: Student's t-test (one sided)
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .795     66     66.0      .023        -
   2     .0148     75     .808     75     57.6      .021       13
   3     .01105    79     .807     52     55.6      .017       16
   5     .00795    83     .806     48     54.2      .021       18
  10     .00535    89     .798     56     54.7      .021       17

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .899     87     87.0      .019        -
   2     .0148     98     .896     49     69.6      .019       20
   3     .01105   104     .909     68     65.1      .019       25
   5     .00795   107     .900     63     61.6      .018       29
  10     .00535   115     .907     55     60.2      .020       31

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .955    108    108.0      .016        -
   2     .0148    121     .957     60     79.2      .015       27
   3     .01105   127     .952     84     72.6      .016       33
   5     .00795   131     .953     52     67.7      .018       37
  10     .00535   138     .955     52     64.1      .018       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 6 - A - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example A - Bell-shaped (truncated normal).  
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .795     66     66.0      .023        -
   2     .0148     75     .794     75     58.4      .026       12
   3     .01105    79     .798     52     55.8      .027       15
   5     .00795    83     .798     48     54.2      .025       18
  10     .00535    89     .810     48     53.6      .031       19

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .893     87     87.0      .025        -
   2     .0148     98     .891     49     69.9      .025       20
   3     .01105   104     .898     68     65.8      .026       24
   5     .00795   107     .896     63     61.6      .028       29
  10     .00535   115     .895     55     60.8      .025       30

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .943    108    108.0      .026        -
   2     .0148    121     .950     60     79.9      .026       26
   3     .01105   127     .953     84     72.2      .025       33
   5     .00795   131     .949     52     66.9      .027       38
  10     .00535   138     .950     52     64.4      .026       40
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 6 - B - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example B - Peaked, right skew
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .782     66     66.0      .026        -
   2     .0148     75     .796     75     57.5      .026       13
   3     .01105    79     .797     52     55.4      .024       16
   5     .00795    83     .799     48     53.7      .023       19 
  10     .00535    89     .801     48     53.6      .027       19

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .882     87     87.0      .027        - 
   2     .0148     98     .893     49     69.8      .028       20
   3     .01105   104     .897     69     65.4      .026       25
   5     .00795   107     .887     63     61.3      .024       30
  10     .00535   115     .897     55     59.6      .026       31

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .941    108    108.0      .023        -
   2     .0148    121     .947     60     79.5      .026       26
   3     .01105   127     .949     84     72.3      .030       33
   5     .00795   131     .944     52     67.0      .027       38
  10     .00535   138     .941     52     63.7      .026       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++




Table 6 - B - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example B - Peaked, right skew.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .945     66     66.0      .025        -       
   2     .0148     75     .956     37     48.9      .025       26
   3     .01105    79     .954     52     44.3      .022       33
   5     .00795    83     .957     32     41.2      .029       38
  10     .00535    89     .963     32     38.5      .029       42

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .983     87     87.0      .028        -
   2     .0148     98     .986     49     57.9      .025       33
   3     .01105   104     .988     34     50.4      .025       42
   5     .00795   107     .989     42     44.5      .025       49
  10     .00535   115     .991     33     41.7      .027       52

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .995    108    108.0      .024        -
   2     .0148    121     .996     60     66.8      .029       38
   3     .01105   127     .997     42     55.3      .023       49
   5     .00795   131     .996     52     47.8      .026       56
  10     .00535   138     .996     39     43.0      .028       60
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 6 - C - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution:  Example C - Rectangular.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .804     66     66.0      .026        -
   2     .0148     75     .818     75     57.5      .026       13
   3     .01105    79     .814     52     55.2      .026       16
   5     .00795    83     .816     48     53.6      .028       19
  10     .00535    89     .806     56     54.4      .027       18

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .902     87     87.0      .025        -   
   2     .0148     98     .907     49     68.7      .025       21
   3     .01105   104     .912     68     64.2      .027       26
   5     .00795   107     .906     63     60.8      .023       30
  10     .00535   115     .915     55     59.4      .026       32

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .954    108    108.0      .023        -
   2     .0148    121     .956     60     78.4      .024       27
   3     .01105   127     .960     84     70.7      .028       35
   5     .00795   131     .956     52     65.8      .024       39
  10     .00535   138     .954     52     63.6      .026       41
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 6 - C - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution:  Example C - Rectangular
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .771     66     66.0      .022        -
   2     .0148     75     .778     75     58.9      .024       11
   3     .01105    79     .776     52     56.8      .022       14
   5     .00795    83     .778     48     55.5      .026       16
  10     .00535    89     .777     56     55.3      .026       18

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .875     87     87.0      .026        -
   2     .0148     98     .885     49     70.7      .026       19
   3     .01105   104     .884     68     67.1      .025       23
   5     .00795   107     .875     63     63.8      .027       27
  10     .00535   115     .884     55     62.6      .023       28

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .931    108    108.0      .025        -
   2     .0148    121     .936     60     81.5      .023       25
   3     .01105   127     .937     84     74.3      .024       31
   5     .00795   131     .939     52     69.0      .022       36
  10     .00535   138     .936     65     66.7      .025       38
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++




Table 6 - D - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example D - J-shaped right skew.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .801     66     66.0      .025        -
   2     .0148     75     .813     75     57.0      .024       14
   3     .01105    79     .817     52     54.6      .024       17
   5     .00795    83     .814     48     53.4      .023       19
  10     .00535    89     .815     48     52.8      .023       20

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .898     87     87.0      .025        -
   2     .0148     98     .902     49     68.9      .023       21
   3     .01105   104     .902     68     64.6      .024       26
   5     .00795   107     .903     63     60.4      .022       31
  10     .00535   115     .910     55     58.3      .023       33

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .946    108    108.0      .023        -
   2     .0148    121     .952     60     78.8      .026       27
   3     .01105   127     .953     84     72.1      .021       33
   5     .00795   131     .950     52     65.6      .024       39
  10     .00535   138     .955     52     62.1      .021       46
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 



Table 6 - D - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example D - J-shaped right skew.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .975     66    66.0       .022        -
   2     .0148     75     .977     37    46.1       .025       30
   3     .01105    79     .979     26    40.7       .023       38
   5     .00795    83     .979     32    36.9       .026       44
  10     .00535    89     .980     32    34.4       .025       48

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .993     87    87.0       .022        -
   2     .0148     98     .994     49    55.1       .023       37
   3     .01105   104     .995     34    46.4       .022       47
   5     .00795   107     .996     42    40.3       .026       54
  10     .00535   115     .996     33    36.8       .025       58

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .998    108   108.0       .022        -
   2     .0148    121     .999     60    64.1       .023       41
   3     .01105   127     .998     42    51.8       .024       52
   5     .00795   131     .999     26    43.5       .023       60
  10     .00535   138     .998     39    38.2       .025       65
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 



Table 6 - E - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example E - Peaked and long-tailed, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .796     66     66.0      .027        -
   2     .0148     75     .808     75     56.8      .026       16
   3     .01105    79     .812     52     54.3      .024       18
   5     .00795    83     .811     48     52.4      .023       21
  10     .00535    89     .817     48     51.8      .023       22

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .887     87     87.0      .022        -
   2     .0148     98     .899     49     68.7      .024       21
   3     .01105   104     .904     68     63.8      .027       27
   5     .00795   107     .901     63     59.6      .023       31
  10     .00535   115     .899     55     58.2      .022       33

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .947    108    108.0      .027        -
   2     .0148    121     .951     60     79.0      .025       27  
   3     .01105   127     .953     84     71.1      .024       34
   5     .00795   131     .952     52     65.3      .024       40
  10     .00535   138     .958     52     60.8      .025       44
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 6 - E - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example E - Peaked long-tailed symmetric.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .984     66     66.0      .023        - 
   2     .0148     75     .987     37     44.5      .025       33
   3     .01105    79     .987     26     39.0      .023       41
   5     .00795    83     .988     32     35.0      .025       47  
  10     .00535    89     .991     24     31.6      .025       52

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .995     87     87.0      .023        -
   2     .0148     98     .997     49     53.2      .027       39
   3     .01105   104     .997     34     44.6      .021       49
   5     .00795   107     .998     42     37.9      .024       56
  10     .00535   115     .998     33     34.0      .023       61

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .999    108    108.0      .021        -
   2     .0148    121    1.000     60     62.8      .026       42
   3     .01105   127    1.000     42     49.7      .024       54
   5     .00795   131    1.000     26     41.1      .025       62
  10     .00535   138    1.000     26     35.7      .027       67
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 6 - F - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example F - Low dome.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .802     66     66.0      .029        -
   2     .0148     75     .811     75     57.6      .032       13 
   3     .01105    79     .803     52     55.5      .026       16
   5     .00795    83     .802     48     54.3      .029       18
  10     .00535    89     .802     56     54.5      .028       17

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .896     87     87.0      .027        -
   2     .0148     98     .905     49     69.3      .027       20 
   3     .01105   104     .906     68     65.0      .026       25
   5     .00795   107     .896     63     61.3      .026       30
  10     .00535   115     .902     55     60.7      .025       30

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .943    108    108.0      .028        -
   2     .0148    121     .950     60     79.1      .026       27
   3     .01105   127     .953     84     71.8      .022       34
   5     .00795   131     .950     52     67.2      .030       38
  10     .00535   138     .951     52     64.0      .028       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 6 - F - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example F - Low dome.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .744     66     66.0      .025        -
   2     .0148     75     .749     75     59.4      .026       10
   3     .01105    79     .754     52     57.8      .026       13
   5     .00795    83     .748     64     56.6      .029       14
  10     .00535    89     .752     56     57.1      .030       13

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .848     87     87.0      .029        -
   2     .0148     98     .858     49     72.1      .025       17
   3     .01105   104     .865     68     68.9      .025       21
   5     .00795   107     .856     63     65.4      .023       22
  10     .00535   115     .858     66     64.7      .029       26

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .917    108    108.0      .028        -
   2     .0148    121     .925     60     82.6      .027       24
   3     .01105   127     .920     84     77.0      .024       29
   5     .00795   131     .921     78     72.1      .024       33
  10     .00535   138     .920     65     68.9      .027       36
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 6 - G - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example G - U-shaped, symmetric
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .809     66     66.0      .026        -
   2     .0148     75     .823     75     57.1      .027       13
   3     .01105    79     .822     52     54.9      .027       17
   5     .00795    83     .807     48     54.1      .023       18
  10     .00535    89     .820     56     54.0      .027       18

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .904     87     87.0      .026        - 
   2     .0148     98     .913     49     68.4      .025       21
   3     .01105   104     .920     68     64.3      .029       26
   5     .00795   107     .914     63     60.7      .026       30
  10     .00535   115     .916     55     59.6      .027       31

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .953    108    108.0      .025        -
   2     .0148    121     .959     60     78.1      .026       28
   3     .01105   127     .957     84     71.3      .026       34
   5     .00795   131     .962     52     65.4      .028       39
  10     .00535   138     .957     52     62.6      .033       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 6 - G - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example G - U-shaped, symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .859     66     66.0      .027        -
   2     .0148     75     .876     37     54.0      .028       18
   3     .01105    79     .880     52     51.1      .028       23
   5     .00795    83     .871     48     49.2      .024       25
  10     .00535    89     .881     48     48.1      .026       27

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .940     87     87.0      .027        -
   2     .0148     98     .942     49     68.6      .027       21
   3     .01105   104     .951     68     59.0      .027       32
   5     .00795   107     .947     42     54.3      .028       38
  10     .00535   115     .953     44     52.6      .028       40

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .972    108    108.0      .026        -
   2     .0148    121     .978     60     73.8      .025       32
   3     .01105   127     .978     42     64.9      .026       40
   5     .00795   131     .977     52     58.6      .026       46
  10     .00535   138     .979     52     55.0      .026       49
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Table 6 - H - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .745     66     66.0      .028        -
   2     .0148     75     .752     75     59.7      .025       10
   3     .01105    79     .755     52     57.7      .027       13
   5     .00795    83     .754     64     56.6      .028       14
  10     .00535    89     .755     56     57.0      .027       14
    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .853     87     87.0      .027        -
   2     .0148     98     .860     49     72.3      .025       15
   3     .01105   104     .865     68     68.4      .026       21
   5     .00795   107     .860     63     64.9      .024       25
  10     .00535   115     .857     66     65.0      .026       25

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .920    108    108.0      .025        -
   2     .0148    121     .926     60     82.7      .025       25
   3     .01105   127     .927     84     76.9      .025       29
   5     .00795   131     .923     78     71.5      .026       34
  10     .00535   138     .922     65     69.1      .029       36
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++




Table 6 - H - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .921     66     66.0      .028        -
   2     .0148     75     .931     37     50.9      .027       23
   3     .01105    79     .934     52     46.6      .026       29
   5     .00795    83     .938     32     43.7      .026       34
  10     .00535    89     .934     40     41.8      .027       37

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .974     87     87.0      .028        -
   2     .0148     98     .973     49     60.6      .027       30
   3     .01105   104     .979     34     53.6      .028       38
   5     .00795   107     .976     42     48.4      .025       44
  10     .00535   115     .980     44     45.3      .029       48

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .990    108     108.0     .028        -
   2     .0148    121     .992     60      68.7     .028       36
   3     .01105   127     .993     42      59.3     .027       45
   5     .00795   131     .993     52      51.5     .029       52
  10     .00535   138     .993     39      47.1     .027       56
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 6 - I - 1 

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .805     66     66.0      .025        - 
   2     .0148     75     .818     75     57.3      .026       13 
   3     .01105    79     .819     52     54.9      .027       17
   5     .00795    83     .814     48     53.2      .026       19
  10     .00535    89     .822     48     53.0      .029       20

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .899     87     87.0      .026        -
   2     .0148     98     .908     49     68.3      .029       21
   3     .01105   104     .910     68     64.1      .029       26
   5     .00795   107     .911     63     60.5      .029       30
  10     .00535   115     .912     55     58.7      .027       33

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .952    108    108.0      .026        -
   2     .0148    121     .954     60     78.6      .029       27
   3     .01105   127     .957     84     70.8      .026       34
   5     .00795   131     .960     52     64.9      .029       40
  10     .00535   138     .958     52     62.1      .028       43
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 6 - I - 2 

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 0.5 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8,  Ptot <= .025 one sided (.05 two sided)   

   1     .025      66     .965     66     66.0      .027        -
   2     .0148     75     .968     37     46.8      .025       29
   3     .01105    79     .970     26     42.0      .024       36
   5     .00795    83     .972     32     37.7      .027       43
  10     .00535    89     .976     32     35.5      .030       46

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      87     .992     87     87.0      .030        -
   2     .0148     98     .996     49     55.9      .024       36
   3     .01105   104     .993     34     47.7      .027       45
   5     .00795   107     .994     42     41.4      .027       52
  10     .00535   115     .996     33     37.6      .028       57

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025     108     .999    108    108.0      .028        -
   2     .0148    121     .999     60     64.6      .025       40
   3     .01105   127     .999     42     52.7      .026       51
   5     .00795   131     .999     52     44.7      .027       59
  10     .00535   138     .998     39     39.6      .025       63
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 7 - A - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example A - Bell-shaped (truncated normal).  
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
  Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19      .843     19     19.0     .022        -
   2     .0148     22      .860     22     16.6     .023       13
   3     .01105    23      .863     14     15.7     .021       17
   5     .00795    24      .852     16     15.3     .025       19
   10    .00535    26      .856     14     15.4     .027       19

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24      .918     24     24.0     .021        -
   2     .0148     27      .930     13     18.8     .022       22
   3     .01105    29      .927     18     17.7     .023       26
   5     .00795    30      .924     18     17.0     .020       29
   10    .00535    32      .932     15     14.6     .026       39

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29      .964     29     29.0     .021        -
   2     .0148     32      .961     16     20.9     .021       28
   3     .01105    34      .966     22     19.3     .023       33
   5     .00795    35      .962     14     17.8     .021       39
   10    .00535    37      .962     15     17.2     .023       41
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 7 - A - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example A - Bell-shaped (truncated normal). 
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .822     19     19.0      .026        -
   2     .0148     22     .850     11     16.5      .027       13
   3     .01105    23     .844     14     15.6      .026       18
   5     .00795    24     .843     16     15.0      .038       21
   10    .00535    26     .844     14     15.1      .033       21

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .902     24     24.0      .026        -
   2     .0148     27     .911     13     19.2      .025       20
   3     .01105    29     .917     18     17.7      .027       26
   5     .00795    30     .920     18     16.4      .029       32
   10    .00535    32     .919     15     16.6      .026       31

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .951     29     29.0      .024        -
   2     .0148     32     .953     16     21.1      .024       27
   3     .01105    34     .957     22     19.3      .026       33
   5     .00795    35     .955     14     18.1      .027       38
   10    .00535    37     .951     15     17.3      .028       40
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 

Table 7 - B - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example B - Unimodal, positive skew.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
----------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19      .823     19     19.0     .023        -
   2     .0148     22      .851     11     16.4     .026       14
   3     .01105    23      .849     14     15.4     .024       19
   5     .00795    24      .843     12     14.7     .023       23
  10     .00535    26      .839     14     14.5     .024       24

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24      .906     24     24.0     .027        -
   2     .0148     27      .913     13     18.7     .025       22
   3     .01105    29      .916     18     17.3     .025       29
   5     .00795    30      .921     18     16.5     .024       31
  10     .00535    32      .924     15     15.8     .023       34

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29      .950     29     29.0     .025        -
   2     .0148     32      .954     16     21.0     .025       28
   3     .01105    34      .955     22     19.0     .025       35
   5     .00795    35      .951     14     17.6     .023       39
  10     .00535    37      .957     15     16.7     .023       42
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 7 - B - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example B - Unimodal, positive skew.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .908     19     19.0      .022        -
   2     .0148     22     .925     11     15.1      .026       21
   3     .01105    23     .925     14     13.8      .031       27
   5     .00795    24     .923     12     12.8      .034       33
  10     .00535    26     .933     10     12.5      .033       34

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .960     24     24.0      .023        - 
   2     .0148     27     .967     13     17.3      .026       28
   3     .01105    29     .972     18     15.5      .026       35
   5     .00795    30     .970     12     14.1      .031       41
  10     .00535    32     .971     12     13.9      .028       42

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .983     29     29.0      .023        -
   2     .0148     32     .986     16     19.2      .027       34
   3     .01105    34     .986     11     16.9      .025       42
   5     .00795    35     .985     14     15.5      .028       47
  10     .00535    37     .988     12     14.1      .026       51
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 7 - C - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution:  Example C - Rectangular (uniform).
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .841     19     19.0      .026        -
   2     .0148     22     .865     22     16.5      .026       13
   3     .01105    23     .852     14     16.1      .030       15
   5     .00795    24     .844     16     15.8      .030       17
  10     .00535    26     .846     14     16.0      .036       16

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .919     24     24.0      .025        -
   2     .0148     27     .926     13     18.9      .026       21
   3     .01105    29     .930     18     18.1      .029       25
   5     .00795    30     .920     18     17.4      .026       27
  10     .00535    32     .931     15     17.0      .031       29

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .964     29     29.0      .026        -
   2     .0148     32     .963     16     21.1      .026       27
   3     .01105    34     .969     22     19.3      .027       33
   5     .00795    35     .962     14     18.3      .027       37
  10     .00535    37     .960     15     17.5      .031       40
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 7 - C - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution:  Example C - Rectangular (uniform).
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .782     19     19.0      .023        -
   2     .0148     22     .804     22     17.0      .027       11 
   3     .01105    23     .795     14     16.5      .029       13
   5     .00795    24     .791     16     16.0      .035       16
  10     .00535    26     .792     14     16.3      .034       14

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .870     24     24.0      .024        -
   2     .0148     27     .876     13     19.8      .026       17
   3     .01105    29     .878     18     19.1      .028       20
   5     .00795    30     .880     18     17.7      .029       26
  10     .00535    32     .888     18     17.8      .027       26
    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .927     29     29.0      .026        -
   2     .0148     32     .928     16     21.8      .024       25
   3     .01105    34     .936     22     20.4      .025       30
   5     .00795    35     .928     21     19.5      .027       33
  10     .00535    37     .930     18     18.8      .029       35
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++




Table 7 - D - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example D - J-shaped, positive skew.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .833     19     19.0      .023        -
   2     .0148     22     .853     11     16.3      .022       14
   3     .01105    23     .851     14     15.2      .021       20
   5     .00795    24     .856     12     14.4      .023       24
  10     .00535    26     .853     12     14.5      .024       24

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .912     24     24.0      .023        -
   2     .0148     27     .915     13     18.6      .023       23
   3     .01105    29     .923     18     17.3      .021       28
   5     .00795    30     .923     12     16.1      .022       33
  10     .00535    32     .927     15     15.5      .022       35

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .947     29     29.0      .023        -
   2     .0148     32     .950     16     21.0      .024       28
   3     .01105    34     .956     22     19.0      .021       34
   5     .00795    35     .956     14     17.4      .019       40
  10     .00535    37     .957     15     16.1      .021       44
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 




Table 7 - D - 2
 
VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example D - J-shaped, positive skew.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .931     19     19.0      .022        -
   2     .0148     22     .949     11     14.5      .026       24
   3     .01105    23     .949     14     12.9      .027       32
   5     .00795    24     .949     12     11.8      .034       38
  10     .00535    26     .951     10     11.6      .031       39

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .974     24     24.0      .026        -
   2     .0148     27     .979     13     16.5      .026       31
   3     .01105    29     .983      9     14.6      .026       39
   5     .00795    30     .981     12     13.3      .025       45
  10     .00535    32     .986     12     12.9      .022       46

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .991     29     29.0      .024        -
   2     .0148     32     .993     16     18.5      .025       36
   3     .01105    34     .995     11     16.0      .026       45
   5     .00795    35     .992     14     14.4      .027       50
  10     .00535    37     .993     12     13.0      .025       55
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ 


 
Table 7 - E - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example E - Peaked and long-tailed, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .828     19     19.0      .024        -
   2     .0148     22     .860     11     16.0      .023       16
   3     .01105    23     .859     14     14.6      .018       23
   5     .00795    24     .862     12     13.6      .018       28
   10    .00535    26     .853     12     13.9      .019       27

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

  1      .025      24     .909     24     24.0      .026        -
  2      .0148     27     .915     13     18.4      .022       23
  3      .01105    29     .930     18     16.7      .021       30
  5      .00795    30     .922     12     15.5      .019       35
  10     .00535    32     .930     12     14.6      .018       39

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

  1      .025      29     .949     29     29.0      .026        -
  2      .0148     32     .952     16     20.9      .021       28
  3      .01105    34     .953     11     18.6      .020       36
  5      .00795    35     .959     14     16.3      .016       44
  10     .00535    37     .954     12     15.3      .019       47
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 7 - E - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example E - Peaked and long-tailed, symmetric.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .956     19     19.0     .025         -
   2     .0148     22     .970     11     13.9     .026        27
   3     .01105    23     .969     14     12.3     .025        35
   5     .00795    24     .967      8     10.7     .037        44
  10     .00535    26     .974      8     10.5     .033        45

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .984     24     24.0     .025         -
   2     .0148     27     .987     13     15.9     .025        34
   3     .01105    29     .991      9     13.9     .027        42
   5     .00795    30     .990     12     12.4     .029        48
  10     .00535    32     .992      9     11.9     .025        50

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .995     29     29.0     .024         -
   2     .0148     32     .997     16     17.9     .025        38
   3     .01105    34     .996     11     15.0     .025        48
   5     .00795    35     .997     14     13.5     .027        53
  10     .00535    37     .998      9     12.0     .024        59
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 


Table 7 - F - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example F - Low dome, symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (0.05 two sided)   

   1     .025      19     .845     19     19.0     .027         -
   2     .0148     22     .865     22     16.7     .031        12
   3     .01105    23     .850     14     16.0     .030        16
   5     .00795    24     .841     16     15.6     .031        18
  10     .00535    26     .842     14     16.1     .037        15

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .920     24     24.0     .024         -
   2     .0148     27     .921     13     19.1     .027        20
   3     .01105    29     .931     18     18.0     .030        25
   5     .00795    30     .921     18     17.2     .028        28
  10     .00535    32     .925     15     17.0     .030        29

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .960     29     29.0     .025         -
   2     .0148     32     .960     16     21.0     .027        28
   3     .01105    34     .965     22     19.5     .027        33
   5     .00795    35     .961     14     18.4     .029        37
  10     .00535    37     .954     15     17.5     .032        40
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 7 - F - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example F - Low dome, symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (0.05 two sided)   

   1     .025      19     .778     19     19.0      .025        -
   2     .0148     22     .804     22     16.9      .027       11
   3     .01105    23     .797     14     16.3      .029       14
   5     .00795    24     .796     16     15.8      .036       17
  10     .00535    26     .792     16     16.4      .031       14

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .872     24     24.0      .024        -
   2     .0148     27     .881     13     19.7      .026       18
   3     .01105    29     .883     18     18.8      .025       22
   5     .00795    30     .881     18     17.6      .035       27
  10     .00535    32     .885     15     17.9      .027       25

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .927     29     29.0      .027        -
   2     .0148     32     .933     16     21.9      .027       24
   3     .01105    34     .932     22     20.6      .025       29
   5     .00795    35     .929     21     19.3      .029       33
  10     .00535    37     .921     18     18.8      .028       35
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 7 - G - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example G - U-shaped symmetric.
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .844     19     19.0      .023        -
   2     .0148     22     .863     22     16.7      .029       12
   3     .01105    23     .850     14     16.2      .034       15
   5     .00795    24     .845     16     16.0      .032       16
  10     .00535    26     .846     14     16.2      .041       15

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .929     24     24.0      .026        -
   2     .0148     27     .933     13     18.9      .027       21
   3     .01105    29     .930     18     18.1      .028       25
   5     .00795    30     .927     18     17.4      .029       28
  10     .00535    32     .931     15     16.9      .037       30

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .961     29     29.0      .026        -
   2     .0148     32     .966     16     21.0      .027       28
   3     .01105    34     .968     22     19.5      .026       33
   5     .00795    35     .961     14     18.3      .031       37
  10     .00535    37     .962     15     17.5      .035       40
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

 
Table 7 - G - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example G - U-shaped symmetric.
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .785     19     19.0      .025        -
   2     .0148     22     .814     22     16.8      .025       12
   3     .01105    23     .807     14     16.2      .026       15
   5     .00795    24     .795     16     15.9      .036       16
   10    .00535    26     .806     14     16.1      .037       15

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .879     24     24.0      .026        -
   2     .0148     27     .882     13     19.5      .023       19
   3     .01105    29     .886     18     18.5      .024       23 
   5     .00795    30     .883     18     17.5      .028       27
   10    .00535    32     .896     15     17.6      .024       27

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .933     29     29.0      .025        -
   2     .0148     32     .933     16     21.7      .026       25
   3     .01105    34     .933     22     20.1      .028       31
   5     .00795    35     .930     21     19.1      .026       34
  10     .00535    37     .934     15     18.3      .028       37
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Table 7 - H - 1

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
---------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .853     19     19.0      .024        -
   2     .0148     22     .864     22     16.6      .024       13  
   3     .01105    23     .859     14     16.2      .029       15
   5     .00795    24     .846     16     15.7      .032       17
  10     .00535    26     .856     14     15.6      .044       18

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .929     24     24.0      .025        -
   2     .0148     27     .929     13     18.9      .025       21
   3     .01105    29     .934     18     18.0      .031       25
   5     .00795    30     .932     18     17.3      .028       28
  10     .00535    32     .935     15     16.6      .035       31         

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .961     29     29.0      .026        -
   2     .0148     32     .963     16     20.9      .028       28
   3     .01105    34     .968     22     19.3      .029       33
   5     .00795    35     .966     14     18.1      .025       38
  10     .00535    37     .962     15     17.4      .036       40
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table 7 - H - 2

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL 
EXPERIMENT PLANS AD MODUM POCOCK                       

Distribution: Example H - Bimodal symmetric
Test: Wilcoxon's two-sample test, t-test on ranks (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
----------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19      .796     19     19.0     .023        -
   2     .0148     22      .811     22     16.8     .027       12
   3     .01105    23      .812     14     16.2     .028       15
   5     .00795    24      .801     16     15.6     .035       18
   10    .00535    26      .799     14     16.1     .035       15

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24      .882     24     24.0     .025        -
   2     .0148     27      .881     13     19.4     .025       19
   3     .01105    29      .885     18     18.7     .027       22
   5     .00795    30      .886     18     17.3     .030       28
   10    .00535    32      .889     15     17.7     .027       26

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29      .929     29     29.0     .024        -
   2     .0148     32      .937     16     21.5     .026       26
   3     .01105    34      .933     22     20.4     .027       30
   5     .00795    35      .931     21     19.1     .026       34
  10     .00535    37      .933     15     18.3     .027       37
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


 
Table 7 - I - 1 

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQUENTIAL EXPERIMENT PLANS 
AD MODUM POCOCK                       

Distribution: Example I - Dome-shaped with outliers
Test: Student's t-test (one sided).
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.


++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
----------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19      .852     19     19.0     .025        -
   2     .0148     22      .859     11     16.5     .027       13
   3     .01105    23      .852     14     15.7     .030       17
   5     .00795    24      .856     12     14.8     .026       22
   10    .00535    26      .862     14     14.9     .030       22

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24      .923     24     24.0     .031        -
   2     .0148     27      .925     13     18.9     .028       21
   3     .01105    29      .935     18     17.6     .028       27
   5     .00795    30      .930     18     16.5     .027       31
   10    .00535    32      .931     15     15.8     .026       34

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29      .960     29     29.0     .027        -
   2     .0148     32      .961     16     21.0     .025       28
   3     .01105    34      .961     22     19.0     .025       34
   5     .00795    35      .959     14     17.7     .026       39
  10     .00535    37      .960     15     16.6     .029       43
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++


Table 7 - I - 2 

VALIDITY TRIAL, PRESENT ADAPTATION OF GROUP SEQENTIAL EXPERIMENT
PLANS AD MODUM POCOCK.

Distribution: Example I - Dome-shaped with outliers Test:
Wilcoxon's two-sample test, t-test on ranks (one sided).  
Alternative hypothesis (H1): Shift (delta) = 1.0 SD.

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 Looks   Nominal  Sample  -------------Realised-------------  Saving,
         LOS,     size,   Power    Sample sizes, Total LOS,   per
         Pnom     max.             Median Mean      Ptot      cent
----------------------------------------------------------------------
    Target: Power >= .8, Ptot <= .025 one sided (.05 two sided)   

   1     .025      19     .919     19     19.0     .027         -
   2     .0148     22     .936     11     14.9     .029        24
   3     .01105    23     .934     14     13.4     .025        29
   5     .00795    24     .934     12     12.2     .035        36
   10    .00535    26     .937     10     12.0     .033        37

    Target: Power >= .9, Ptot <= .025 one sided (.05 two sided)

   1     .025      24     .967     24     24.0     .027         -
   2     .0148     27     .971     13     16.9     .026        30
   3     .01105    29     .975     18     15.1     .028        37
   5     .00795    30     .972     12     13.8     .030        43
  10     .00535    32     .976     12     13.3     .028        46

    Target: Power >= .95, Ptot <= .025 one sided (.05 two sided) 

   1     .025      29     .987     29     29.0     .026         -
   2     .0148     32     .990     16     18.7     .027        36
   3     .01105    34     .989     11     16.3     .026        44
   5     .00795    35     .991     14     14.9     .030        49
  10     .00535    37     .989     12     13.7     .028        53
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

            
                       XXXXXXXXXXXX

                  Appendix 1, page 1

APPENDIX 1: THE EFFECT OF DELAYED TESTING.


To investigate the effect of accidents that might threaten to
mar a group sequential plan during realisation, one has to
suggest likely scenarios.

One simple scenario would be a delay of one interim test, which
for some force majeure reason cannot be performed on time, i.e.
when a group has reached the correct size.

In such a case, one could choose to cancel that test, and to
simplify the plan with respect to number of groups (and tests),
so that e.g. a five-test plan were transformed into a three-test
plan of correct structure.

Another, perhaps more practical solution would be to continue
adding individuals until the test can be performed, which should
take place at first opportunity. It would then seem natural to
subtract from the following group to obtain the planned sample
size for next test, thereafter to follow the original plan.

Concentrating on five-group plans with targeted power 0.90 and
targeted Ptot of 0.05, one sided, I have investigated the effect
of delayed statistical testing.  Delays leading to increase of a
group with 1/4, alternatively 1/2, 3/4 and '1/1' (the latter,
simply cancellation of one test) were simulated, using the
example distributions described previously. The effect of
delaying the final test is obvious and was not investigated.
Realised total level of significance, power and mean sample size
were studied.

Appendix tables 1 and 2 shows part of the results. Using the
bell-shaped distribution and the t-test, the effect of increases
of 1/4 and 1/2 of the size of one group does not much influence
the performance of the design. The same story was told when
using the unimodal, skewed distribution.  In both cases,
targeted power and level of significance were preserved. We
notice modest increases of average sample size (up to one and a
half unit, about three per cent).

In contrast, increases of 3/4 and '1/1' (cancellation of one
test) led to markedly increased average sample sizes: up to
about three units in the first case, and five in the second
case.  However, power and total level of significance were still
in order.

Moreover, for increases of 1/2 of group size or more, we notice
that alteration of group sizes during the first half of the plan
is more harmful than alteration later on.  In fact, the largest
average sample sizes were produced by delaying the first or the
second interim test.

For a 'traditional' fixed sample experiment with the same power
and significance level as in Appendix table 1, we would use 72
individuals, see Table 4-A-1.  A three group plan would be
expected to include on the average about 58 individuals, see
Table 4-A-1, while the five group plan with delays such as
described is seen to involve on the average about 55
individuals.  

                      Appendix 1, page 2

To generalize, it appears that delays of this kind do not at all
threaten to destroy the experiment. We must expect increases of
average sample sizes, but otherwise the performance of the plan is
untouched. This holds for large delays or even cancellation of one
test.

To check the above conclusion, data similar to those of Appendix
table 1 were collected for all the example distribution, for
targeted power 0.8, 0.9 and 0.95  and significance level of 0.05
(one sided and two sided). A few of the results are shown in
Appendix table 3. The table is restricted to the case of
targeted power 0.9 and targeted total significance level of
0.05.  To save space, only the largest observed sample sizes
were tabulated, see Appendix table 3.  The upper two rows have
been extracted from Appendix tables 1 and 2.

In all cases, the relative increase of average sample sizes were
in line with those above: Delays equalling 1/4 and 1/2 group
size had negligible effect, while larger delays reduced the
performance of the five-group plan to that of four- or three
group plans. Power and level of significance were preserved.

In nearly all cases, largest realised sample sizes 
emerged when delaying the first or the second interim test.

All taken together, we are justified in concluding that group
sequential plans ad modum Pocock are robust for irregularities
with respect to delay involving one group (one test), as long as
the final test is performed when planned total sample sizes are
reached. The conlusion is based on simulation of plans involving
five groups (five tests), and does not necessarily hold for
plans with smaller or larger number of groups.

Thus, there is no need to abandon a group sequential plan a.m.
Pocock if for some compelling reason one interim test has been
delayed or cancelled. Targeted power and targeted total
significance will still be there. The plan will be somewhat
weaker with respect to realised sample size, but that is all.
The results also suggest that neither should the plan be
abandoned even if more than one test has been delayed. The effect
need not be very large, and can easily be investigated by
computer simulation. The author would be happy to assist with
this.

A scenario where one test has to be performed ahead of
schedule could also be imagined. Preliminary trials suggest
that performing one test when the group in question has
reached only 1/2 or 3/4 of scheduled size does no harm and
may in fact slightly increase performance, i.e. lead to
lower average sample sizes than the original plan.

                          XXXXXX     


Table  App.1.1

GROUP SEQUENTIAL EXPERIMENT PLANS A. M. POCOCK: THE EFFECT  OF
DELAYED TESTING, LEADING TO INCREASE OF GROUP AND SAMPLE SIZE AT
ONE INTERIM TEST.

Distribution A: Bell-shaped (truncated normal). Shift = 0.5 SD.
Test: Student's t-test, one sided. Planned group size: 18
No of tests: Five. Target: Power >= .9, Ptot <= .05, one sided.
No of simulations: 10000.-

+++++++++++++++++++++++++++++++++++++++++++++++++++++++
Sample size at testing. ----------Realised-----------
Hyphen: Sample size     Ptot   Power   --Mean sample--
of original plan                       size   st.error
------------------------------------------------------
                   Original plan
   
 18  36  54  72  92    .0506   .9155   49.27   .257

      Delay = 1/4 of group size, rounded to 5.

 23   -   -   -   -    .0475   .9127   49.46   .250
  -  41   -   -   -    .0451   .9136   49.77   .250
  -   -  59   -   -    .0466   .9161   49.73   .254 
  -   -   -  77   -    .0459   .9143   49.88   .259 
      
        Delay = 1/2 of group size = 9.

 27   -   -   -   -    .0443   .9169   49.83   .239
  -  45   -   -   -    .0491   .9151   50.98   .247
  -   -  63   -   -    .0479   .9156   50.64   .258
  -   -   -   81  -    .0439   .9157   49.87   .262

      Delay = 3/4 of group size, rounded to 14.

 32   -   -   -   -    .0383   .9145   52.22   .227
  -  50   -   -   -    .0421   .9104   53.04   .245
  -   -  68   -   -    .0452   .9126   51.73   .264
  -   -   -   86  -    .0445   .9126   50.59   .272
     
    Delay: 1/1 of group size, omitting one test 
          'x' symbol shows test omitted
  
  x   -   -   -   -    .0381   .9073   54.79   .212
  -   x   -   -   -    .0406   .9156   54.90   .247
  -   -   x   -   -    .0400   .9146   52.51   .275
  -   -   -   x   -    .0452   .9047   51.52   .285
++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table App.1.2

GROUP SEQUENTIAL EXPERIMENT PLANS A. M. POCOCK: THE EFFECT  OF
DELAYED TESTING, LEADING TO INCREASE OF GROUP AND SAMPLE SIZE AT
ONE INTERIM TEST.

Distribution B: Unimodal positive skew. Shift = 0.5 SD.
Wilcoxon's two-sample test (t-test version), one sided.
Planned group size: 18
No of tests: Five. Target: Power >= .9, Ptot <= .05, one sided.
No of simulations: 10000.-

+++++++++++++++++++++++++++++++++++++++++++++++++++++++
Sample size at testing. ----------Realised-----------
Hyphen: Sample size     Ptot   Power   --Mean sample--
of original plan                       size   st.error
------------------------------------------------------
                   Original plan
   
 18  36  54  72  92     .0533  .9867   37.88  .204 

      Delay = 1/4 of group size, rounded to 5.

 23   -   -   -   -     .0518  .9848   38.21  .193
  -  41   -   -   -     .0485  .9855   38.84  .203
  -   -  59   -   -     .0502  .9852   38.40  .207
  -   -   -  77   -     .0524  .9844   38.02  .208
      
        Delay = 1/2 of group size = 9.

 27   -   -   -   -     .0561  .9822   39.38  .181
  -  45   -   -   -     .0481  .9850   40.08  .203   
  -   -  63   -   -     .0509  .9852   38.82  .214
  -   -   -   81  -     .0544  .9828   38.26  .214

      Delay = 3/4 of group size, rounded to 14.

 32   -   -   -   -     .0446  .9813   42.03  .168
  -  50   -   -   -     .0499  .9838   42.27  .212 
  -   -  68   -   -     .0475  .9838   39.78  .226
  -   -   -   86  -     .0457  .9825   38.62  .221
     
 Delay:'1/1' of group size, i.e. omitting one test 
          'x' symbol shows test omitted
  
  x   -   -   -   -     .0442  .9843   45.18  .156
  -   x   -   -   -     .0499  .9847   43.87  .219
  -   -   x   -   -     .0506  .9834   40.94  .240
  -   -   -   x   -     .0467  .9825   38.85  .233
+++++++++++++++++++++++++++++++++++++++++++++++++++++



Table App.1.3

GROUP SEQUENTIAL EXPERIMENT PLANS A. M. POCOCK: THE EFFECT OF
DELAYED TESTING, SUMMARY.  LARGEST REALISED MEAN SAMPLE SIZES
FOR EXPERIMENT PLANS INVOLVING DELAY OF ONE INTERIM TEST,
LEADING TO INCREASE OF GROUP SIZE WITH 1/4, 1/2, 3/4; OR '1/1'-
CANCELLATION OF ONE TEST (*)

'Best test' used (Student's t-test or Wilcoxon's test,
t-test version, (**)). No of tests: Five.  Shift = 0.5 SD.
Target: Power >= .9, Ptot <= .05, one sided. (***)

++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Example    No delay,-        Delay, fraction of group
distri-    original     ----------------------------------
bution     plan         1/4        1/2       3/4       1/1
------------------------------------------------------------  
A t-test   49.3 .26   49.9 .26  51.0 .25  53.0 .25  54.9 .25
B W- "     37.9 .20   38.8 .20  40.1 .20  42.3 .21  45.2 .16
C t- "     49.7 .26   50.3 .25  51.3 .25  52.9 .24  55.1 .21
D W- "     33.9 .18   35.2 .18  36.3 .18  39.0 .14  42.1 .13
E W- "     31.9 .17   33.5 .16  34.8 .14  37.8 .13  41.4 .12
F t- "     49.9 .25   50.8 .26  52.7 .27  53.1 .25  55.6 .22
G W- "     45.1 .26   45.6 .24  47.0 .24  48.7 .23  51.2 .20
H W- "     39.4 .22   40.9 .21  41.9 .21  44.0 .22  46.9 .20
I W- "     34.9 .19   35.8 .18  37.1 .19  39.2 .20  42.6 .13
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
 
(*) In nearly all cases, largest realised sample sizes
emerged when delaying the first or the second interim test.

(**) 'Best test' is the one that showed highest realised power
for the respective example distribution, according to the
tables numbered '4-', of the main tables section.

(***) The two upper rows were extracted from Appendix tables
1 and 2.


                       XXXXXX



                     Appendix 2 page 1

APPENDIX 2: ON A PRIORI INFORMATION.

The procedure summarised on page of the main section, and based
on Tables 1, 2 and 3 is simple as well as safe, but it is lacking
in one respect: The planning is supposed to take place in a
'vacuum', with little regard to previous information about the
medical or biological problem under investigation.

In real life, the investigator has a priori information from
literature as well as from informal preliminary experiments.
The experiment to be published often takes place in a situation
where the investigator is able to guess pretty well the
conclusion, the purpose of the experiment being to vindicate a
hypothesis (H1) and to convince the reader.

The risk of a negative experiment (tests 'not significant')
is of course small in such situations, and hence we may
expect that the realised sample size will be perhaps about
half of the stipulated maximum, and about two thirds of the
sample size of a comparable fixed sample experiment.

As a rule, prior information is difficult to include in a
statistical computation. However, there is one important
exception: The hypothetical shift (reference improvement,
standardised difference).  On page 5 of the main text, it is
recommended to proceed with the smallest shift that is of
practical importance. However, it is perfectly possible and
often more fruitful to consider a RANGE of expected shifts.

One would like a plan where there is sufficient power to
discover a shift whether it is small or large.
It may be said that experiment planning using the smallest
realistic shift ensures just that. True enough, but
everything comes at a price. The purpose of sequential
plans is to reduce the number of individuals involved, and
so we should turn every stone to achieve this. One way to
take is to employ the hypothetical shift MOST LIKELY to
occur, instead of the SMALLEST shift of interest.

The tool needed for this is a table where power is
tabulated according to shift and maximal sample size. 
A table covering the case of a bell-shaped distribution is
given below (Table App 2.1). Note intended level of
significance, which is 0.05 one sided. Appendix table 2.1
is made far larger than necessary in practice. 
Using the MEDSEQ programs, an experimenter can easily 
construct a table tailored to the experiment in question.

An example will show its usefulness. Consider an experiment
where we expect a shift in the range of 0.7 - 0.9. We feel
that the result most likely to emerge is 0.8, but we
would also like to be able to discover a shift of 0.7 with
reasonable probability.

                    Appendix 2 page 2

Planning the experiment on basis of a standardised difference of
0.7, using Table 1 and Table 2 of the main section (valid for all
distributions likely to be encountered), and aiming at a
power of 0.9 (90 per cent), we arrive at a maximal sample size
of 49. - If we instead use Table App.2.1 below, (valid for
bell-shaped distributions) we can read directly that a maximal
sample size of 45 individuals would give a power of 90.1 -

Next, imagine that we use a reference shift of 0.8. Then,
according to Table App.2.1, a maximal sample size of 35 would
render the demanded power of 90.1. Now, with this maximal
sample size, if the realised experiment should demonstrate
a shift of 0.7, how probable is it that the statistical
test will flag such a difference as being significant?
Again, directly from the table, we find that the power in
such a situation would be 81.0 per cent.  Moreover, we note
that there is more than a 50/50 chance of a significant
test, even if the realised shift should be as small as 0.5.

Therefore, if the latter plan is accepted, we can 'save' 10
individuals per sample, or nearly 1/4, compared with the
former plan. Still, there is reasonable power to detect
lower shifts.

However, the reader may remember a remark on page 10
concerning unnecessary large maximal sample sizes: In such
cases, early termination will offer compensation.  Is not
the whole idea of sequential plans to let the DATA
determine realised sample size?

Certainly, but this type of compensation is not complete.
Also, in the real world, when money and manpower is being
discussed, it is important to present a realistic maximal
sample size. If this is set too high the experiment could
be rejected on grounds of economy or time.

Table App.2.1 below is valid for bell-shaped distributions only,
when using Student's t-test. If skewed or tail-heavy
distributions are expected, one can construct a small power
table of one's own, based on the W-test and the expected
distribution. The necessary data can be produced by the
MEDSEQ programs.

An example of the latter sort of data is given as Table
App.2.2. The table is intended to be an illustration, and is
much larger than needed in practice. Repeating the plans
sketched above using Table App.2.2. instead of App.2.1 is a
very worthwile exercise. We may that in addition conclude that
taking the form of the expected distribution into consideration
can give a handsome payoff in terms of reduction of maximal
sample size.

                        XXX
 
Table App.2.1

GROUP SEQUENTIAL DESIGN AD MODUM POCOCK: POWER ACCORDING TO
MAXIMAL SAMPLE SIZE AND SHIFT. 

Distribution: Example A, bell-shaped (truncated normal).
Maximal number of tests/groups: Five.
Intended total level of significance, Ptot, is .05
Nominal level of sign. for each test, Pnom, is .0159
Test type: Student's t-test, ordinary version.
Number of simulations (replications): 10000.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++            
Maximal                         Shift
sample       ----------------------------------------------
size         .3    .4    .5    .6    .7    .8    .9    1.0
-----------------------------------------------------------
  15         15.9  21.7  28.3  36.5  46.1  55.6  65.8  73.8
  20         18.3  26.9  35.5  46.7  57.7  68.3  77.8  85.8
  25         21.3  31.2  42.1  56.0  67.0  77.9  86.7  92.2
  30         23.5  35.4  48.6  63.2  75.6  85.3  91.2  96.2
  35         26.1  39.9  54.6  68.9  81.0  90.1  95.1  98.3
  40         28.1  43.9  59.6  74.9  86.7  93.2  97.0  99.1
  45         32.0  48.1  65.1  79.7  90.1  95.6  98.5  99.5
  50         33.4  51.1  68.9  83.5  92.8  97.3  99.2
  55         36.1  55.1  73.2  87.1  94.3  98.3  99.5
  60         38.7  58.3  77.1  89.6  96.2  99.1
  70         44.5  64.8  82.6  93.4  97.9  99.5
  80         48.2  71.1  86.5  96.0  99.0
  90         52.1  76.1  90.5  97.5  99.5
 100         56.7  79.7  93.6  98.4
 110         59.2  83.0  95.0  99.2
 120         63.6  85.9  96.4  99.5                          
 130         67.1  89.0  97.6  
 140         70.8  90.3  98.5
 150         73.0  92.1  99.0                    Standard
 160         76.3  93.7  99.1                    errors
 170         77.5  95.0  99.5                    ---------
 180         80.3  96.0                          15.0  .36
 190         82.4  97.0                          20.0  .40
 200         84.1  97.4                          30.0  .46
 220         87.4  98.5                          40.0  .49
 240         90.3  99.0                          50.0  .50
 260         92.2  99.4                          60.0  .49
 280         94.1                                70.0  .46
 300         95.3                                80.0  .40
 340         97.3                                85.0  .36
 380         98.5                                90.0  .30
 420         99.1                                95.0  .22
 460         99.4                                99.0  .10  
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++



Table App.2.2

GROUP SEQUENTIAL DESIGN AD MODUM POCOCK: POWER ACCORDING 
TO MAXIMAL SAMPLE SIZE AND SHIFT.

Distribution: Example B, unimodal, positive skew.
Maximal number of tests/groups: Five.
Intended total level of significance, Ptot, is .05
Nominal level of sign. for each test, Pnom, is .0159
Test: Wilcoxon's two-group test, t-test version.
Number of simulations (replications): 10000.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++            
Maximal                         Shift
sample       ----------------------------------------------
size         .3    .4    .5    .6    .7    .8    .9    1.0
-----------------------------------------------------------
  15         23.1  35.5  44.5  54.4  63.5  70.9  77.7  84.1
  20         27.6  40.3  51.7  64.3  73.1  81.5  87.7  92.8
  25         31.1  45.3  60.5  71.7  81.8  88.5  93.6  96.0
  30         36.0  51.9  66.7  79.5  87.9  97.7  96.6  98.3
  35         39.3  57.7  74.1  85.2  92.2  96.2  98.4  99.3
  40         43.8  63.2  78.6  88.8  95.5  97.9  99.3  99.7
  45         48.1  68.7  83.1  92.2  96.9  98.9  99.8
  50         51.4  71.7  85.7  94.2  97.9  99.4
  55         54.5  75.7  89.2  96.1  98.8  99.7
  60         59.1  78.7  91.5  97.6  99.3
  70         64.5  85.4  94.8  98.6  99.8
  80         71.4  89.4  97.4  99.5
  90         74.8  91.6  98.2  99.7
 100         79.2  94.3  99.0  
 110         82.7  95.9  99.5                    Standard
 120         84.6  97.3  99.8                    errors
 130         87.1  98.2                          --------
 140         89.6  98.3                          15.0  .36
 150         91.5  98.9                          20.0  .40   
 160         93.3  99.4                          30.0  .46
 170         94.0  99.7                          40.0  .49
 180         95.2                                50.0  .50
 190         96.0                                60.0  .49
 200         97.3                                70.0  .46
 220         97.9                                80.0  .40
 240         98.6                                85.0  .36
 260         99.2                                90.0  .30
 280         99.3                                95.0  .22
                                                 99.0  .10
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

                    END OF MANUSCRIPT   







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