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Common Statistical
Methods for
Clinical Research:
with SAS® Examples
Glenn A. Walker
SAS Publishing
More praise for this new edition
“This book is an extension and improvement to the excellent first edition, which appeared
in 1996. Each chapter has an introduction covering a specific statistical method and gives
examples of where the method is used. The introduction is followed by a synopsis
presenting the necessary and significant information for the reader to get a good
understanding of the statistical method. Excellent examples are given, followed by the
SAS code for the example. Detailed annotations make the SAS output easy to understand.
The book also gives numerous extensions for the methods.
Dr. Walker has certainly used his many years of consulting experience, his teaching
experience, and his understanding of SAS to produce an even better book that is equally
understandable and helpful to the novice as well as the experienced statistician. Each will
benefit from this insightful journey into statistics and the use of SAS, whether as a
teaching tool or a refresher. I can recommend this book wholeheartedly.”
CommonStatistical Methods
for Clinical Research
with SAS Examples
®
Glenn A. Walker
58086
The correct bibliographic citation for this manual is as follows: Walker, Glenn A. 2002. Common Statistical Methods
®
for Clinical Research with SAS Examples, Second Edition. Cary, NC: SAS Institute Inc.
®
Common Statistical Methods for Clinical Research with SAS Examples, Second Edition
SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513.
SAS Publishing provides a complete selection of books and electronic products to help customers use SAS software to
its fullest potential. For more information about our e-books, e-learning products, CDs, and hardcopy books, visit the
SAS Publishing Web site at www.sas.com/pubs or call 1-800-727-3228.
®
SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS
Institute Inc. in the USA and other countries. ® indicates USA registration.
Other brand and product names are trademarks of their respective companies.
Table of Contents
Chapter 23 – Exercises
23.1 Introduction............................................................................................................................. 381
23.2 Exercises .................................................................................................................................. 381
23.3 Appropriateness of the Methods ........................................................................................... 383
23.4 Summary.................................................................................................................................. 387
This second edition expands the first edition with the inclusion of new sections,
examples, and extensions of statistical methods described in the first edition only
in their most elementary forms. New methods sections include analysis of
crossover designs (Chapter 9) and multiple comparison methods (Appendix D).
Chapters that present repeated measures analysis (Chapter 8), linear regression
(Chapter 10), analysis of covariance (Chapter 11), the chi-square test (Chapter 16),
and logistic regression (Chapter 20) have been notably expanded, and 50% more
examples have been added throughout the book. A new chapter of exercises has
also been added to give the reader practice in applying the various methods
presented. Also new in this edition is an introduction to α-adjustments for interim
analyses (Chapter 2).
Although many of the new features will have wide appeal, some are targeted to the
more experienced data analyst. These include discussion of the proportional odds
model, the clustered binomial problem, collinearity in multiple regression, the use
of time-dependent covariates with Cox regression, and the use of generalized
estimating equations in repeated measures analysis. These methods, which are
based on more advanced concepts than those found in most of the book, are
routinely encountered in data analysis applications of clinical investigations and, as
such, fit the description of ‘common statistical methods for clinical research’.
However, so as not to overwhelm the less experienced reader, these concepts are
presented only briefly, usually by example, along with references for further
reading.
The examples have been updated to Version 8 of SAS, however, the programming
statements used have been kept ‘portable’, meaning that most can be used in earlier
versions of SAS as they appear in the examples, unless otherwise noted. This
includes the use of portable variable and data set names, despite accommodation
for use of long names beginning with Version 8. Because SAS is
xii Common Statistical Methods for Clinical Research with SAS Examples
not the main focus of this book but is key to efficient data analysis, programming
details are not included here, but they can be found in numerous references cited
throughout the book. Many of these references are other books in the Books by
Users program at SAS, which provide the details, including procedure options, use
of ODS, and the naming standards that are new in Version 8. For statistical
programming, my favorites include Categorical Data Analysis Using the SAS
System, Second Edition, by Stokes, Davis, and Koch (2000) and Survival
Analysis Using the SAS System, A Practical Guide, by Paul Allison (1995).
I welcome and appreciate reader comments and feedback through the SAS
Publications Web site.
Glenn A. Walker
July 2002
Preface xiii
This book was written for those involved in clinical research and who may, from
time to time, need a guide to help demystify some of the most commonly used
statistical methods encountered in our profession.
All too often, I have heard medical directors of clinical research departments
express frustration at seemingly cryptic statistical methods sections of protocols
which they are responsible for approving. Other nonstatisticians, including medical
monitors, investigators, clinical project managers, medical writers and regulatory
personnel, often voice similar sentiment when it comes to statistics, despite the
profound reliance upon statistical methods in the success of the clinical program.
For these people, I offer this book (sans technical details) as a reference guide to
better understand statistical methods as applied to clinical investigation and the
conditions and assumptions under which they are applied.
For the clinical data analyst and statistician new to clinical applications, the
examples from a clinical trials setting may help in making the transition from other
statistical fields to that of clinical trials. The discussions of 'Least-Squares' means,
distinguishing features of the various SAS® types of sums-of-squares, and
relationships among various tests (such as the Chi-Square Test, the Cochran-
Mantel-Haenszel Test and the Log-Rank Test) may help crystalize the analyst's
understanding of these methods. Analysts with no prior SAS experience should
benefit by the simplifed SAS programming statements provided with each example
as an introduction to SAS analyses.
This book may also aid the SAS programmer with limited statistical knowledge in
better grasping an overall picture of the clinical trials process. Many times
knowledge of the hypotheses being tested and appropriate interpretation of the
SAS output relative to those hypotheses will help the programmer become more
efficient in responding to the requests of other clinical project team members.
Finally, the medical student will find the focused presentation on the specific
methods presented to be of value while proceeding through a first course in
biostatistics.
For all readers, my goal was to provide a unique approach to the description of
commonly used statistical methods by integrating both manual and computerized
solutions to a wide variety of examples taken from clinical research. Those who
learn best by example should find this approach rewarding. I have found no other
book which demonstrates that the SAS output actually does have the same results
as the manual solution of a problem using the calculating formulas. So ever
reassuring this is for the student of clinical data analysis!
xiv Common Statistical Methods for Clinical Research with SAS Examples
Each statistical test is presented in a separate chapter, and includes a brief, non-
technical introduction, a synopsis of the test, one or two examples worked
manually followed by an appropriate solution using the SAS statistical package,
and finally, a discussion with details and relevant notes.
Chapters 1 and 2 are introductory in nature, and should be carefully read by all
with no prior formal exposure to statistics. Chapter 1 provides an introduction to
statistics and some of the basic concepts involved in inference-making. Chapter 2
goes into more detail with regard to the main aspects of hypothesis testing,
including significance levels, power and sample size determination. For those who
use analysis-of-variance, Appendix C provides a non-technical introduction to
ANOVA methods. The remainder of the book may be used as a text or reference.
As a reference, the reader should keep in mind that many of the tests discussed in
later chapters rely on concepts presented earlier in the book, strongly suggesting
prerequisite review.
Many of the examples are based on actual clinical trials which I have analyzed. In
all cases, the data are contrived, and in many cases fictitious names are used for
different treatments or research facilities. Any resemblence of the data or the tests'
results to actual cases is purely coincidental.
Glenn A. Walker
May 1996
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abject condition and the universal contempt in which they were held,
the degraded state of their religion was sufficiently apparent.
A priest acted as the exponent of the tenets of the Christian belief to
the king. Christianity, he said, believes in the eternity of God and the
creation of the world out of nothing, and that all men are descended
from Adam; it accepts as true all that the Torah and the Scriptures of
Judaism teach, but holds as its fundamental dogma, the incarnation of
the Deity through a virgin of the Jewish royal house. The Son of God,
the Father and the Holy Ghost form a unit. This trinity is venerated by
the Christians as a unity, even though the phrase appears to indicate a
threefold personality. Christians are to be considered as the real
Israelites, and the twelve apostles take the place of the twelve tribes.
The mind of the king was as little gratified by the answer of the
Christian as by that of the Philosopher, the reply not being in accordance
with the dictates of reason. The Christian, he thought, should have
adduced positive, incontrovertible proofs, which would satisfy the human
intellect. He, therefore, felt it his duty to seek further for true religion.
Thereupon he inquired of a Mahometan theologian as to the basis of
the faith of Islam. The Moslem believe, as he affirmed, in the unity and
eternity of God, and in the creatio ex nihilo; but reject anthropomorphic
conceptions. Mahomet was the last and most important among the
prophets, who summoned all people to the faith, and promised to the
faithful a paradise with all the delights of eating, drinking, and
voluptuous love, but to the infidels, the eternal fire of damnation. The
truth of Islam depends upon the fact that no man is capable of
producing so remarkable a book as the Koran, or even a single one of its
Suras. To him also the king replied that the fact of the intimate
intercourse of God with mortals must rest upon undeniable proofs,
which the internal evidence for the divine origin of the Koran does not
afford, for even if its diction is able to convince an Arab, it has no power
over those who are unacquainted with Arabic.
As both the Christian and the Moslem had referred their religions to
Judaism in order to verify the historic basis of each, the truth-seeking
king at length determined to overcome his prejudice against Judaism,
and to make inquiries of a Jewish sage. The latter made the following
statement of the tenets of his creed, in reply to the request of the king:
"The Jews believe in the God of their ancestors, who delivered the
Israelites from Egypt, performed miracles for their sake, led them into
the Holy Land, and raised up prophets in their midst—in short, in all that
is taught in the Holy Scriptures." Thereupon the king of the Chazars
replied, "I was right, then, in not asking of the Jews, because their
wretched, low condition has destroyed every reasonable idea in them.
You, O Jew, should have premised that you believe in the Creator and
Ruler of the world, instead of giving me so dry and unattractive a mass
of facts, which are of significance only to you." The Jewish sage replied:
"This notion that God is the Creator and Ruler of the universe requires a
lengthy demonstration, and the philosophers have different opinions on
the matter. The belief, however, that God performed miracles for us
Israelites demands no proof, as it depends upon the evidence of
undoubted eye-witnesses." Starting from this point, the religious
philosopher, Jehuda Halevi, has an easy task to unfold proofs of the
truth and divine character of Judaism. Philosophy discards God and
religion entirely, not knowing what place to assign to them in the world.
Christianity and Islam turn their backs on reason, for they find reason in
opposition to the cardinal doctrines of their religions. Judaism, on the
contrary, starts from a statement of observed facts, which reason cannot
possibly explain away. It is quite compatible with reason, but assigns to
reason its limits, and does not accept the conclusions of reason, often
degenerating into sophistry, when certainty can be attained in another
way.
In his correct view of the value of speculative thought, Jehuda
Halevi stood alone in his own time, and anticipated many centuries. The
thinkers of his time, Jewish, Mahometan and Christian, Rabbi, Ulema
and Churchman, bowed the knee to Aristotle, whose philosophical
judgments upon God and His relation to the world they placed above
Holy Writ, or at least they strained and subtilized the Biblical verses until
they expressed a philosophical idea, and thus they became at once
believers and sceptics. Jehuda Halevi alone had the courage to point out
the limits set by nature to human thought, and to proclaim, "Thus far
shalt thou go, and no further." Philosophy has no right to attack well-
accredited facts, but must accept them as undeniable truths; it must
start with them for bases, bringing to bear its power of co-ordinating the
facts and illuminating them by the aid of reason. Just as in the realm of
nature the intellect dare not deny actual phenomena when they present
themselves, however striking and contrary to reason they may appear,
but must strive to comprehend them, so must it act when touching on
the question of the knowledge of God. This excellent and irrefutable
idea, which of late years, after many wanderings in the labyrinth of
philosophy, has at length discovered a way for itself, was first enunciated
by Jehuda Halevi. In a poem, which is as beautiful as its matter is true,
he thus expresses his opinion of the Greek spirit which studious disciples
of philosophy so eagerly affected:
This is the keynote of all the songs of Zion. But in how many and in
what various ways does the poet skilfully manipulate his subject! What a
wealth of sentiments, images and devices does he develop! The ancient
days of Israel are idealized in his verses; the people of his own age at
one time appear invested with the thorny crown of a thousand
sufferings, and at another with the glittering diadem of a glorious hope.
The contents of his lyrics unwittingly penetrate into the soul of the
reader, and hurry him to and fro, from pain and woe to hope and
rejoicing, and for a long time the deep impression remains, intermingled
with feelings of enthusiasm and conviction.
The bard, who was thus inspired by the cause of his nation, busied
himself in communicating to his brethren this deep longing for
Jerusalem, and in arousing them to arrange some plan of return. One
poem, in elevated and lovely strains, encouraged the people, "The
Distant Dove," to leave the fields of Edom and Arab (Christendom and
Mahometan countries), and to seek its native nest in Zion. But no
answering echo was awakened. It was a sublime, ideal conception that
enabled the pious poet-philosopher even to dream of so daring a flight.
The soul of Jehuda Halevi was drawn by invisible cords to Israel's
ancient home, and he could not detach it from them. When he had
concluded his immortal work, the dialogue of the Chozari (about 1141),
he entertained serious thoughts of starting on his holy journey. He made
no slight sacrifices to this remarkable, if somewhat adventurous, resolve.
He exchanged a peaceful, comfortable life for one of disquietude and
uncertainty, and left behind his only daughter and his grandson, whom
he loved most dearly. He gave up his college which he had established in
Toledo, and parted from a circle of disciples whom he loved as sons, and
who in turn revered him as a father. He bade farewell to his numerous
friends, who, without envy, praised him as a distinguished scholar. All
this in his estimation was of little value in comparison with his love of
God and the Holy Land. He desired to bring his heart as an offering to
the sacred place, and to find his grave in sanctified earth.
Provided with ample means, Jehuda Halevi started on his journey,
and his passage through Spain resembled a triumph. His numerous
admirers in the towns through which he passed outvied each other in
attentions to him. With a few faithful companions he took passage on
board a vessel bound for Egypt. Confined in the narrow wooden cabins,
where there was no room either to sit or to lie down, a mark for the
coarse jests of the rough mariners, sea-sick and in weak health, his soul
yet lost none of its power to elevate itself into a brighter sphere. His
ideals were his most trusty companions. The storm which tossed the
ships about on the waves like a plaything, when "between him and
death there intervened only a board," unlocked the store of song within
his breast. Of the sea he sang songs which for faithfulness of description
and depth of feeling have few equals:
The closing adventures of his life, beyond the fact that he was at
Tyre and at Damascus, are not known. The Jewish community at Tyre
rendered great honor to him, and the memory of this treatment was
impressed on his grateful heart. In a poem to his Tyrian friend he
grieves over his faded hopes, his misspent youth, and his present
wretchedness, in verses which cannot be read without stirring up
emotions at the despondency of this valorous soldier. In Damascus he
sang his swan-song, the glorious song of Zion, which, like the Psalms of
Asaph, awake a longing for Jerusalem. The year of his death and the
site of his grave are both unknown. A legend has it that a Mahometan
horseman rode over him as he was chanting his mournful Lay of Zion.
Thus reads a short epitaph which an unknown admirer wrote for him:
"Honor, Faith, and Gentleness, whither have ye flown?
Vainly do I seek you; Learning, too, is gone!
'Hither are we gathered,' they reply as one,
'Here we rest with Judah.'"
This, however, does not convey the smallest portion of what this
ethereal and yet powerful character was. Jehuda Halevi was the
spiritualized image of the race of Israel, conscious of itself, seeking to
display itself, in its past and in its future, in an intellectual and artistic
form.
In Spain Jewish culture had arrived at its zenith, and had reached its
highest perfection in the greatest of the neo-Hebraic poets. In France
the beginnings of culture now became manifest. The reigns of the two
kings of the house of Capet, Louis VI and VII (1108–1180), were as
favorable to the Jews as that of Louis the Pious. The congregations in
the north of France lived in the comfort and prosperity that arouses
envy, their granaries were filled with corn, their cellars with wine, their
warehouses with merchandise, and their coffers with gold and silver.
They owned houses and fields and vineyards, cultivated either by
themselves or by Christian servants. It is said that half of Paris, which at
that time was not yet a city of very great importance, belonged to Jews.
The Jewish congregations were recognized as independent corporations,
and had their own mayor, with the title of Provost (præpositus), who
was invested with authority to guard the interests of his people, and to
arrest Christian debtors and compel them to pay their Jewish creditors.
The Jewish provost was chosen by the community, and his election was
ratified by the king or the baron to whom the town was tributary; Jews
frequented the court, and held office. Jacob Tam, the greatest rabbinical
authority of this time, was highly respected by the king. Jewish
theologians freely disputed with the clergy upon religious questions, and
openly expressed their honest opinions about the Trinity, the Virgin Mary,
the worship of saints, about auricular confession and the miracle-
working powers of relics.
Under these favorable circumstances of unrestricted tolerance, the
Jewish sages of the north of France were able to follow in the path
which Rashi had marked out for them. To understand and explain the
Talmud in its entirety became a passion with the French Jews. Death
had snatched away the commentator on the Talmud in the midst of his
labors at Troyes; his pupils exerted themselves to complete whatever
had been left unfinished by him. He had bequeathed to his school a
spirit of indefatigable research and close inquiry, of acute dialectics, and
the art of fine discrimination, and they richly increased their inheritance.
The correct and precise understanding of the Talmud was so sacred a
matter to the pupils of Rashi, that they did not hesitate to subject the
interpretations of their master to a severe critical revision. But, on the
other hand, their veneration for him was so great that they did not
venture to offer their opinions independently, but attached them to the
commentaries of Rashi as "Supplements" (Tossafoth). From this
circumstance they were called the Tossafists. They supplied the
omissions of Rashi, and also emended and expanded the explanations
given by him. The chief characteristic of the method of the Tossafists is
their independence of the authorities, they subjected all opinions to the
scrutiny of their own reason. Their profound scholarship and great
erudition comprehended the immense Talmudic literature and its maze
of learned discussions and arguments with clearness and precision. Their
penetrating intellect displayed remarkable ingenuity in resolving every
argument and every idea into its original elements, distinguishing
thoughts that appeared to be similar, and reconciling such as seemed to
conflict. It is almost impossible to convey to the mind of the uninitiated
any satisfactory notion of the critical acumen of the Tossafists. They
solved the most difficult logical problems with the greatest ease, as if
they were the simple examples set to children. The unyielding material
of the Talmud became quite malleable under their hands, and they
fashioned surprising Halachic (legal) shapes and substances. For the
circumstances of modern times they found numerous analogies on
record, which a superficial examination would never have discovered.
The circle of the earliest Tossafists was composed chiefly of the
relatives of Rashi, viz.: his two sons-in-law, Meïr ben Samuel of Rameru,
a small town near Troyes, and Jehuda ben Nathan (Riban); later, his
three grandsons, Isaac, Samuel and Jacob Tam, the sons of Meïr; and
finally a German, Isaac ben Asher Halevi (Riba) of Speyer, also
connected with the family of Rashi.
The school of the Tossafists divided the study of the Talmud into two
branches: theoretical discussion leading to a thorough comprehension of
the text of the Talmud (Chiddushim), and practical application of the
results of such study in the civil laws, in the laws of marriage, and in the
religious ritual (Pesakim, Responsa). This ingenious method revealed
new legal ordinances.
The study of the Talmud fully occupied the intellectual powers of the
Jews of the north of France and the Rhine, and prevented the cultivation
of other studies. Poetry did not thrive in a region where logic wielded
the scepter, and where the imagination was brought into play only in
order to invent new complications and hypothetical cases. The
interpretation of Scripture was also treated in a Talmudical manner. Most
of the Tossafists were Bible exegetes, but they did not pay much
attention to the exact meaning of the text, studying it by means of
Agadic interpretations. Tossafoth were written to elucidate the
Pentateuch as well as the Talmud. Only two men can be recorded as
famous exceptions, who returned from exegesis according to the Agadic
method (Derush) to the strict and rational elucidation of the text
(Peshat); these are Joseph Kara and Samuel ben Meïr (about 1100-
1160). Both of these have the greater importance, since they were in
opposition to their fathers, who adhered to the Midrashic system of
interpretation. Joseph Kara was the son of Simon Kara, a compiler of
Agadic pieces, the author of the Yalkut; and Samuel ben Meïr had been
taught by his grandfather Rashi to pay great respect to the Agada. Both
of them forsook the old way, and sought an explanation of the text in
strict accordance with rules of grammar. Samuel, who completed Rashi's
commentary to Job and to some of the treatises of the Talmud, had so
thoroughly convinced his grandfather of the correctness of rational
exegesis, that he had declared that if strength were granted him, he
would alter his commentary to the Pentateuch in accordance with other
exegetical principles. Samuel, called Rashbam, wrote, in this temperate
style, a commentary to the Pentateuch and the Five Megilloth; and
Joseph Kara wrote commentaries on the books of the Prophets and the
Hagiographa. Samuel ben Meïr, in his interpretation of Holy Writ, sought
for the sense and the connection of the text, and did not shrink from
explanations at variance with the Talmud, or in harmony with the views
of the Karaites.
CHAPTER XII.
PERSECUTIONS DURING THE SECOND CRUSADE
AND UNDER THE ALMOHADES.
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