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Handbook of Survival Analysis 1st Edition John P. Klein
Digital Instant Download
Author(s): John P. Klein, Hans C. van Houwelingen, Joseph G. Ibrahim,
Thomas H. Scheike
ISBN(s): 9781466555679, 146655567X
Edition: 1
File Details: PDF, 4.88 MB
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Language: english
 Chapman & Hall/CRC
Handbooks of Modern
Statistical Methods

Handbook of
Survival Analysis
Edited by

John P. Klein
Hans C. van Houwelingen
Joseph G. Ibrahim
Thomas H. Scheike
Handbook
of Survival
Analysis
 Chapman & Hall/CRC
Handbooks of Modern Statistical Methods

Series Editor
Garrett Fitzmaurice
Department of Biostatistics
Harvard School of Public Health
Boston, MA, U.S.A.

Aims and Scope

The objective of the series is to provide high-quality volumes covering the state-of-the-art in the theory
and applications of statistical methodology. The books in the series are thoroughly edited and present
comprehensive coherent and uni¿ed summaries of speci¿c methodological topics from statistics. The
chapters are Zritten by the leading researchers in the ¿eld and present a good balance of theory and
application through a synthesis of the key methodological developments and examples and case studies
using real data.

The scope of the series is wide, covering topics of statistical methodology that are well developed and
¿nd application in a range of scienti¿c disciplines. The volumes are primarily of interest to researchers
and graduate students from statistics and biostatistics, but also appeal to scientists from ¿elds where the
methodology is applied to real problems, including medical research, epidemiology and public health,
engineering, biological science, environmental science, and the social sciences.

Published Titles

Longitudinal Data Analysis

Edited by Garrett Fitzmaurice, Marie Davidian,
Geert Verbeke, and Geert Molenberghs

Handbook of Spatial Statistics

Edited by Alan E. Gelfand, Peter J. Diggle,
Montserrat Fuentes, and Peter Guttorp

Handbook of Markov Chain Monte Carlo

Edited by Steve Brooks, Andrew Gelman,
Galin L. Jones, and Xiao-Li Meng

Handbook of Survival Analysis

Edited by John P. Klein, Hans C. van Houwelingen,
Joseph G. Ibrahim, and Thomas H. Scheike
 Chapman & Hall/CRC
Handbooks of Modern
Statistical Methods

Handbook
of Survival
Analysis

Edited by

John P. Klein
Hans C. van Houwelingen
Joseph G. Ibrahim
Thomas H. Scheike
CRC Press
Taylor & Francis Group
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Contents

Preface ix

About the Editors xi

List of Contributors xiii

I Regression Models for Right Censoring 1

1 Cox Regression Model 5

Hans C. van Houwelingen and Theo Stijnen

2 Bayesian Analysis of the Cox Model 27

Joseph G. Ibrahim, Ming-Hui Chen and Danjie Zhang, and Debajyoti Sinha

3 Alternatives to the Cox Model 49

Torben Martinussen and Limin Peng

4 Transformation Models 77
Danyu Lin

5 High-Dimensional Regression Models 93

Jennifer A. Sinnott and Tianxi Cai

6 Cure Models 113

Yingwei Peng and Jeremy M. G. Taylor

7 Causal Models 135

Theis Lange and Naja H. Rod

II Competing Risks 153

8 Classical Regression Models for Competing Risks 157

Jan Beyersmann and Thomas H. Scheike

9 Bayesian Regression Models for Competing Risks 179

Ming-Hui Chen, Mário de Castro, Miaomiao Ge, and Yuanye Zhang

10 Pseudo-Value Regression Models 199

Brent R. Logan and Tao Wang

v
vi Contents

11 Binomial Regression Models 221

Randi Grøn and Thomas A. Gerds

12 Regression Models in Bone Marrow Transplantation – A Case Study 243

Mei-Jie Zhang, Marcelo C. Pasquini, and Kwang Woo Ahn

III Model Selection and Validation 263

13 Classical Model Selection 265

Florence H. Yong, Tianxi Cai, L.J. Wei, and Lu Tian

14 Bayesian Model Selection 285

Purushottam W. Laud

15 Model Selection for High-Dimensional Models 301

Rosa J. Meijer and Jelle J. Goeman

16 Robustness of Proportional Hazards Regression 323

John O’Quigley and Ronghui Xu

IV Other Censoring Schemes 341

17 Nested Case-Control and Case-Cohort Studies 343

Ørnulf Borgan and Sven Ove Samuelsen

18 Interval Censoring 369

Jianguo Sun and Junlong Li

19 Current Status Data: An Illustration with Data on Avalanche Victims 391

Nicholas P. Jewell and Ruth Emerson

V Multivariate/Multistate Models 413

20 Multistate Models 417

Per Kragh Andersen and Maja Pohar Perme

21 Landmarking 441
Hein Putter

22 Frailty Models 457

Philip Hougaard

23 Bayesian Analysis of Frailty Models 475

Paul Gustafson

24 Copula Models 489

Joanna H. Shih
Contents vii

25 Clustered Competing Risks 511

Guoqing Diao and Donglin Zeng

26 Joint Models of Longitudinal and Survival Data 523

Wen Ye and Menggang Yu

27 Familial Studies 549

Karen Bandeen-Roche

VI Clinical Trials 569

28 Sample Size Calculations for Clinical Trials 571

Kristin Ohneberg and Martin Schumacher

29 Group Sequential Designs for Survival Data 595

Chris Jennison and Bruce Turnbull

30 Inference for Paired Survival Data 615

Jennifer Le-Rademacher and Ruta Brazauskas

Index 633
Preface

This volume examines modern techniques and research problems in the analysis of lifetime
data analysis. This area of statistics deals with time-to-event data which is complicated not
only by the dynamic nature of events occurring in time but also by censoring where some
events are not observed directly, but rather they are known to fall in some interval or range.
Historically survival analysis is one of the oldest areas of statistics dating its origin to
classic life table construction begun in the 1600s. Much of the early work in this area involved
constructing better life tables and long tedious extensions of non-censored nonparametric
estimators. Modern survival analysis began in the late 1980s with pioneering work by Odd
Aalen on adapting classical Martingale theory to these more applied problems. Theory based
on these counting process martingales made the development of techniques for censored and
truncated data in most cases easier and opened the door to both Bayesian and classical
statistics for a wide range of problems and applications.
In this volume we present a series of chapters which provide an introduction to the ad-
vances in survival analysis techniques in the past thirty years. These chapters can serve four
complementary purposes. First, they provide an introduction to various areas in survival
analysis for graduates students and other new researchers to this field. Second, they provide
a reference to more-established investigators in this area of modern investigations into sur-
vival analysis. Third, with a bit of supplementation on counting process theory this volume
is useful as a text for a second or advanced course in survival analysis. We have found
that the instructor of such a course can pick and choose chapters in areas he/she deems
most useful to the students or areas of interest to the instructor. Lastly, these chapters can
help practicing statisticians pick the best statistical method to analyze their survival data
experiment.
To help with reading the volume we have grouped chapters into six parts, each with a
brief introduction by the editor. These parts are:

I Regression Models for Right Censoring

II Competing Risks
III Model Selection and Validation
IV Other Censoring Schemes
V Multivariate/Multistate Models
VI Clinical Trials

We believe that the chapters and topics presented here provide a good overview of the
current status of survival analysis and will further inspire research into this area.
We would like to express our thanks to all the authors who contributed their time and
effort to this volume. Without these contributions the volume would not be possible. A
special thank you goes to Professor van Houwelingen who took upon himself much of the
work of putting the authors’ LaTeX and pdf files into a book format.

ix
About the Editors

John P. Klein received his Ph.D. in 1980 from the University of Missouri. His thesis work
was on dependent competing risks and safe dose estimation with dependent competing risks.
While a student, he was a summer intern for two summers at the Oak Ridge National Labs
working on modeling the effects of low-level radiation on mice.
Upon graduation, Dr. Klein joined the faculty in the Department of Statistics at the
Ohio State University (OSU) where he rose to the rank of professor. While at OSU he
was the statistician for the Clinical Research Center and Director of Statistics for the
OSU Comprehensive Cancer Center. In 1987 he was a Gæsteprofessor at the University of
Copenhagen which led to a long and fruitful collaboration with faculty there.
In 1993 Dr. Klein moved to Medical College of Wisconsin to be professor and director
of the Division of Biostatistics. Since that time, he has been the statistical director of the
Center for Blood and Marrow Transplantation. Recently, he has been appointed statistical
director of the Clinical and Translational Research Institute of Southeast Wisconsin and
the statistical director of the MCW Cancer Center. He is recognized as a leading expert in
the analysis of bone marrow transplant data.
Dr. Klein is the author of 230 research papers, about half of which are in the statistical
literature. He is a co-author of Survival Analysis: Techniques for Censored and Truncated
Data, a standard graduate text. He is an associate editor of Biometrics, Life Time Data
Analysis, Dysphagia, and The Iranian Journal of Statistics. He is an elected member of the
International Statistical Institute and a fellow of the American Statistical Institute.

Hans C. van Houwelingen received his Ph.D. in Mathematical Statistics from the
University of Utrecht, The Netherlands, in 1973. He stayed at the Mathematics Department
in Utrecht until 1986. During that time his theoretical research interest was Empirical Bayes
methodology as developed by Herbert Robbins. His main contribution was the finding that
Empirical Bayes rules could be improved by monitorization.
On the practical side he was involved in collaborations with researchers in Psychology,
Chemistry and Medicine. The latter brought him to Leiden in 1986 where he was appointed
chair and department head in Medical Statistics at the Leiden Medical School, which was
transformed into the Leiden University Medical Center (LUMC) in 1996.
Together with his Ph.D. students he developed several research lines in logistic regres-
sion, survival analysis, meta-analysis, statistical genetics and statistical bioinformatics. In
the meantime the department grew into the Department of Medical Statistics and Bioin-
formatics, which also includes the chair and staff in Molecular Epidemiology.
He was editor-in-chief of Statistica Neerlandica and served on the editorial boards of
Statistical Methods In Medical Research, Lifetime Data Analysis, Biometrics, Biostatistics,
Biometrical Journal, and Statistics & Probability Letters. He is an elected member of ISI, fel-
low of ASA, honorary member of the International Society for Clinical Biostatistics (ISCB),
Dutch Statistical Society (VVS) and ANed, the Dutch Region of the International Biometric
Society (IBS).
Dr. van Houwelingen retired on January 1, 2009. On that occasion he was appointed
Knight in the Order of the Dutch Lion. After his retirement he wrote, together with Hein

xi
xii About the Editors

Putter, the Chapman & Hall monograph Dynamic Prediction in Clinical Survival Analysis,
published in 2012.

Joseph G. Ibrahim is alumni distinguished professor of biostatistics at the University

of North Carolina, Chapel Hill (UNC). Dr. Ibrahim’s areas of research focus on Bayesian
inference, missing data problems, and genomics. He received his Ph.D. in statistics from
the University of Minnesota in 1988. With over 19 years of experience working in cancer
clinical trials, Dr. Ibrahim directs the UNC Center for Innovative Clinical Trials. He is
also the director of graduate studies in UNC’s Department of Biostatistics, as well as the
program director of the cancer genomics training grant in the department. He has directed
or co-directed 27 doctoral students and 7 post-doctoral fellows. He is currently the editor
of the Applications and Case Studies Section of the Journal of the American Statistical
Association and currently serving as the associate editor for several other statistical journals.
Dr. Ibrahim has published over 230 research papers, mostly in top statistical journals. He
also has published two advanced graduate-level books on Bayesian survival analysis and
Monte Carlo methods in Bayesian computation. He is an elected fellow of the American
Statistical Association and the Institute of Mathematical Statistics, and an elected member
of the International Statistical Institute.

Thomas H. Scheike received his Ph.D. in Mathematical Statistics from the University
of California at Berkley in 1993, and received a doctoral degree in Statistics (Dr. Scient)
from the University of Copenhagen in 2002. He has been in the Department of Biostatistics
at the University of Copenhagen since 1994.
His research interest is in biostatistics with particular emphasis on survival analyses and
longitudinal data. He has written the Springer monograph, Dynamic Regression Models for
Survival Data (2006) with Torben Martinussen. Dr. Scheike has been involved in several
R-packages (timereg, HaploSurvival, mets) that have been developing recent methods in
survival analyses for the biostatistical community.
Dr. Scheike was editor-in-chief of Scandinavian Journal of Statistics, and served on the
editorial boards of Journal of the Royal Statistical Society, Lifetime Data Analysis, and
Statistica Sinica.
List of Contributors

Editors
John P. Klein Joseph G. Ibrahim
Division of Biostatistics Department of Biostatistics
Medical College of Wisconsin University of North Carolina
Milwaukee, WI, USA Chapel Hill, NC, USA

Hans C. van Houwelingen Thomas H. Scheike

Leiden University Medical Center University of Copenhagen
Leiden, The Netherlands Copenhagen, Denmark

Authors
Kwang Woo Ahn Ruta Brazauskas
Division of Biostatistics Division of Biostatistics
Medical College of Wisconsin Medical College of Wisconsin
Milwaukee, WI, USA Milwaukee, WI, USA

Per Kragh Andersen Tianxi Cai

Department of Biostatistics Department of Biostatistics
University of Copenhagen Harvard School of Public Health
Copenhagen, Denmark Boston, MA, USA

Karen Bandeen-Roche Ming-Hui Chen

Department of Biostatistics Department of Statistics
Johns Hopkins Bloomberg School of Public University of Connecticut
Health Storrs, CT, USA
Baltimore, MD, USA
Mário de Castro
Jan Beyersmann Instituto de Ciências Matemáticas e de
Freiburg University Medical Center and Computação
Ulm University Universidade de São Paulo
Freiburg and Ulm, Germany São Carlos-SP, Brazil

Ørnulf Borgan Guoqing Diao

University of Oslo George Mason University
Oslo, Norway Fairfax, VA, USA

xiii
xiv List of Contributors

Ruth Emerson Purushottam W. Laud

University of California Division of Biostatistics
Berkeley, CA, USA Medical College of Wisconsin
Milwaukee, WI, USA
Miaomiao Ge
Jennifer Le-Rademacher
Clinical Bio Statistics
Boehringer Ingelheim Pharmaceuticals, Inc. Division of Biostatistics
Medical College of Wisconsin
Ridgefield, CT, USA
Milwaukee, WI, USA
Thomas A. Gerds Junlong Li
Department of Biostatistics Department of Biostatistics
University of Copenhagen Harvard University
Copenhagen, Denmark Boston, MA, USA

Jelle J. Goeman Danyu Lin

Leiden University Medical Center Department of Biostatistics
Leiden, The Netherlands University of North Carolina
Chapel Hill, NC, USA
Randi Grøn Brent R. Logan
Department of Biostatistics Division of Biostatistics
University of Copenhagen Medical College of Wisconsin
Copenhagen, Denmark Milwaukee, WI, USA

Paul Gustafson Torben Martinussen

Department of Statistics Department of Biostatistics
University of British Columbia University of Copenhagen
Vancouver, BC, Canada Copenhagen, Denmark

Rosa J. Meijer
Philip Hougaard Leiden University Medical Center
Biometric Division, Lundbeck Leiden, The Netherlands
Valby, Denmark
Kristin Ohneberg
Joseph G. Ibrahim Institute of Medical Biometry and Medical
Department of Biostatistics Informatics
University of North Carolina University Medical Center Freiburg
Chapel Hill, NC, USA Freiburg, Germany

Chris Jennison John O’Quigley

University of Bath Université Pierre et Marie Curie - Paris VI
Bath, UK Paris, France

Marcelo C. Pasquini
Nicholas P. Jewell Division of Hematology and Oncology
University of California Medical College of Wisconsin
Berkeley, CA, USA Milwaukee, WI, USA

Theis Lange Limin Peng

Section of Social Medicine Department of Biostatistics and
Department of Public Health, University Bioinformatics
of Copenhagen Emory University
Copenhagen, Denmark Atlanta, GA, USA
List of Contributors xv

Yingwei Peng Jeremy M. G. Taylor

Queen’s University University of Michigan
Kingston, Ontario, Canada Ann Arbor, MI, USA
Maja Pohar Perme Lu Tian
Department of Biostatistics and Medical Stanford University School of Medicine
Informatics Stanford, CA, USA
University of Ljubljana
Ljubljana, Slovenia Bruce Turnbull
Hein Putter Cornell University
Department of Medical Statistics and Ithaca, NY, USA
Bioinformatics Hans C. van Houwelingen
Leiden University Medical Center
Leiden University Medical Center
Leiden, The Netherlands Leiden, The Netherlands
Naja H. Rod
Tao Wang
Section of Social Medicine
Department of Public Health, University Division of Biostatistics
Medical College of Wisconsin
of Copenhagen
Copenhagen, Denmark Milwaukee, WI, USA

Sven Ove Samuelsen L.J. Wei

University of Oslo Harvard School of Public Health
Oslo, Norway Boston, MA, USA
Thomas H. Scheike
Ronghui Xu
University of Copenhagen
Copenhagen, Denmark University of California
San Diego, CA, USA
Martin Schumacher
Institute of Medical Biometry and Medical Wen Ye
Informatics Department of Biostatistics
University Medical Center Freiburg University of Michigan
Freiburg, Germany Ann Arbor, MI, USA
Joanna H. Shih
National Cancer Institute Florence H. Yong
Bethesda, MD, USA Harvard School of Public Health
Debajyoti Sinha Boston, MA, USA
Department of Statistics
Florida State University Menggang Yu
Tallahassee, FL, USA Department of Biostatistics and Medical
Informatics
Jennifer A. Sinnott
University of Wisconsin
Department of Biostatistics
Madison, WI, USA
Harvard School of Public Health
Boston, MA, USA
Donglin Zeng
Theo Stijnen University of North Carolina
Leiden University Medical Center Chapel Hill, NC, USA
Leiden, The Netherlands
Jianguo Sun Danjie Zhang
Department of Statistics Department of Statistics
University of Missouri University of Connecticut
Columbia, MO, USA Storrs, CT, USA
xvi List of Contributors

Mei-Jie Zhang Yuanye Zhang

Division of Biostatistics Novartis Institutes for BioMedical Research
Medical College of Wisconsin Inc.
Milwaukee, WI, USA Cambridge, MA, USA
 Part I

Regression Models for Right

Censoring

1
2 Part I

In Part 1 we present statistical methods for right-censored and left-truncated survival

data. For this type of data it is assumed that there is a single event which causes death
or failure of an individual sampling unit. These sample units could be humans or animals
subjected to some type of treatment or they could be mechanical or electronic units. Here
if the time-to-failure is T then we are interested in making an inference about the survival
function S(t) = P r[T > t]. In engineering applications this function is called the “reliability
function.” In the sequel we focus on the biological applications of methods.
For many applications the time-to-failure is not observable for all individuals in the study
but partial information that the event time is longer than some censoring time is all that
is available. Such observations are called right-censored observations and the information
they give us is simply that the failure time for an individual is beyond their censoring time.
There are many types of right censoring. There is type I censoring where each subject
has assigned to it a fixed censoring time after which observation on the subject stops.
This censoring scheme is used in reliability applications to shorten the on-study time or in
biological studies when the observational window is fixed. For type II censoring the number
of failures is fixed and the censoring time is random. This scheme is used most often in
engineering applications to reduce the on-study time. Finally there is progressive censoring
where what is observed is the smaller of the event time T and a random censoring time C.
The censoring time C, commonly the lost-to-follow-up time, reflects when the individual
drops out of the study or stops being followed. Most analysis assumes that this censoring
time is non-informative or independent of the survival time. Censoring is non-informative
if there is no information on the survival time, T , available from the magnitude of the
censoring time.
In some cases in addition to being right-censored the data is left-truncated. Data is said
to be left-truncated if only those potential subjects that have had some truncating event
occur at a time τ are at risk at any point in time beyond τ . The classic example is the
Channing house study which examined the survival probabilities for senior citizens in a
nursing home. In that study at a given time, t0 , only subjects who enter the home at an
age prior to t0 , are considered at risk for death at this age, and any patient with an entry
age greater than t0 is not included in the risk set. Since left truncation simply modifies the
risk set, the methods developed for right-censored data are usually the same as those for
left-truncated right-censored data.
Inference techniques for survival data can trace their roots to three key publications. The
first is the paper by Kaplan and Meier (1958) which developed a non-parametric estimator
of the survival function (see Section 1.1.2). This “Kaplan-Meier” estimator was a modern
version of the classical life tables used in actuary science and developed by Edmond Halley
in 1693 (yes the famous comet discoverer). The second work is the paper by David Cox
(1972) which is the centerpiece of this first set of chapters and discussed briefly below.
The third and perhaps most important work is the development of the theory of counting
processes and their use in survival analysis by Odd Aalen. His pioneering work on counting
processes and martingales, starting with his 1975 Ph.D. thesis, has had profound influence
on survival analysis techniques. Inferences for fundamental quantities associated with cu-
mulative hazard rates in survival analysis and models for analysis of event histories are
typically based on Aalen’s work.
The Cox model or the proportional hazards model is perhaps the most common method
in survival analysis. This model is based on modeling the hazard rate λ(t|Z). Here the
hazard rate is the rate at which individuals are experiencing the event, namely
d ln(S(t|Z)) f (t|Z)
λ(t|Z) = − = .
dt S(t|Z))
Here S(T |Z) (f (T |Z)) is the survival probability (density) given a vector Z of covariates.
Part I 3

The Cox model in its most widely used formulation assumes that we can write λ(t|Z) as

λ(t|Z) = λ0 (t) exp{β t Z}

where β is a vector of parameters and λ0 (t) is a baseline hazard. Note that for this model
if we have two individuals with two sets of covariates that
λ(t|Z1 ) λ0 (t) exp{β t Z1 }
= = exp{β t (Z1 − Z2 )}
λ(t|Z2 ) λ0 (t) exp{β t Z2 }

which is independent of t. Hence this is called the “proportional hazards model.”

The Cox model is the most popular regression model for survival data. Its properties
can be derived using the counting process techniques of Aalen. There are inference packages
for it in almost every statistical package. It can be extended quite easily to time-dependent
covariates and models for multistate models or models with random effects.
In Chapter 1 we present a paper by van Houwelingen and Stijnen on the classical es-
timation of the Cox model and in Chapter 2 a paper by Ibrahim et al. on the Bayesian
approach to estimation for this model. In Chapter 5 we present a paper by Sinnott and Cai
on how to make inference about model parameters in the Cox model when the number of
parameters is very large.
Chapters 3 and 4 examine alternatives to the Cox model for right-censored data. In
Chapter 3 we present a paper by Martinussen and Peng which surveys non-proportional
hazards models including Aalen’s additive hazards model, the accelerated failure time model
and Quartile regression models. In Chapter 4 Lin surveys a class of transformation models
for right-censored data. For such models we assume that the model is given by H(T ) =
β t Z +  where H() is an unspecified increasing function, β a set of regression coefficients
and  a random error with a parametric distribution such as the extreme-value distribution
or the standard logistic error distribution. Special cases include the proportional hazards
and proportional odds model. Lin examines this class of models in a variety of sampling
and modeling situations.
Chapters 6 and 7 show how the basic ideas of the Cox model can be extended to more
complicated models. In Chapter 6 Peng and Taylor look at cure models. In such models an
unknown fraction of the population cannot fail and as such is cured of the disease under
study. Finally, Chapter 7 by Lange and Rod looks at the use of the Cox model as a causal
model.

Bibliography
Aalen, O. O. (1975), Statistical Inference for a Family of Counting Processes, PhD thesis,
University of California, Berkeley.
Cox, D. R. (1972), ‘Regression models and life-tables’, Journal of the Royal Statistical
Society - Series B 34, 187–220.
Halley, E. (1693), ‘An estimate of the degrees of the mortality of mankind, drawn from
curious tables of the births and funerals at the city of Breslaw with an attempt to ascertain
the price of annuities upon lives’, Philosophical Transactions 17, 596–610.
Kaplan, E. and Meier, P. (1958), ‘Nonparametric estimation from incomplete observations’,
Journal of the American Statistical Association 43, 457–481.
1
Cox Regression Model

Hans C. van Houwelingen and Theo Stijnen

Leiden University Medical Center

CONTENTS
1.1 Basic statistical concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.1.1 Survival time and censoring time . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.1.2 The Kaplan-Meier estimator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.1.3 The hazard function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
1.2 The proportional hazards (Cox) model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.3 Fitting the Cox model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.4 Example: NKI breast cancer data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.5 Martingale residuals, model fit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Continued example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Influential data points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1.6 Extensions of the data structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.6.1 Delayed entry, left truncation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.6.2 Time-dependent covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.6.3 Continued example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1.7 Beyond proportional hazards assumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.7.1 Stratified models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.7.2 Time-varying coefficients, Schoenfeld residuals . . . . . . . . . . . . . . . . . . . . . . . 20
1.7.3 Continued example . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.7.4 Final remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

1.1 Basic statistical concepts

1.1.1 Survival time and censoring time
To set up the framework for survival data with right censoring, two random variables need
to be defined

Tsurv : the survival time, Tcens : the censoring time.

The censoring time Tcens is often denoted by C. Different censoring mechanisms can be
distinguished. A common one for clinical data is administrative censoring, where the cen-
soring time is determined by the termination of the study. For most purposes it suffices to
consider the censoring to be random. The crucial condition for statistical analysis is that
survival time Tsurv and censoring time Tcens are independent. In the presence of explanatory

5
Exploring the Variety of Random
Documents with Different Content
 Journalism - Term Paper
Spring 2023 - Department

Prepared by: Dr. Garcia

Date: August 12, 2025

Background 1: Comparative analysis and synthesis

Learning Objective 1: Study tips and learning strategies
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
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- Note: Important consideration
Formula: [Mathematical expression or equation]
Learning Objective 2: Problem-solving strategies and techniques
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Learning Objective 3: Experimental procedures and results
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Learning Objective 4: Ethical considerations and implications
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Learning Objective 5: Problem-solving strategies and techniques
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Case studies and real-world applications
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 6: Diagram/Chart/Graph]
Remember: Statistical analysis and interpretation
• Key terms and definitions
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- Example: Practical application scenario
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Note: Literature review and discussion
• Case studies and real-world applications
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[Figure 8: Diagram/Chart/Graph]
Example 8: Comparative analysis and synthesis
• Study tips and learning strategies
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Remember: Best practices and recommendations
• Problem-solving strategies and techniques
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[Figure 10: Diagram/Chart/Graph]
Appendix 2: Theoretical framework and methodology
Practice Problem 10: Assessment criteria and rubrics
• Assessment criteria and rubrics
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- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Current trends and future directions
• Assessment criteria and rubrics
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- Example: Practical application scenario
- Note: Important consideration
Important: Statistical analysis and interpretation
• Fundamental concepts and principles
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Remember: Ethical considerations and implications
• Interdisciplinary approaches
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[Figure 14: Diagram/Chart/Graph]
Note: Learning outcomes and objectives
• Comparative analysis and synthesis
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- Example: Practical application scenario
- Note: Important consideration
Definition: Statistical analysis and interpretation
• Study tips and learning strategies
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• Problem-solving strategies and techniques
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Example 17: Best practices and recommendations
• Theoretical framework and methodology
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Practice Problem 18: Experimental procedures and results
• Key terms and definitions
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- Example: Practical application scenario
Remember: Literature review and discussion
• Ethical considerations and implications
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- Example: Practical application scenario
Background 3: Problem-solving strategies and techniques
Definition: Experimental procedures and results
• Comparative analysis and synthesis
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- Note: Important consideration
[Figure 21: Diagram/Chart/Graph]
Practice Problem 21: Literature review and discussion
• Current trends and future directions
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- Example: Practical application scenario
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Important: Literature review and discussion
• Comparative analysis and synthesis
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Key Concept: Problem-solving strategies and techniques
• Critical analysis and evaluation
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- Note: Important consideration
[Figure 24: Diagram/Chart/Graph]
Practice Problem 24: Critical analysis and evaluation
• Interdisciplinary approaches
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- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Statistical analysis and interpretation
• Ethical considerations and implications
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- Note: Important consideration
Remember: Experimental procedures and results
• Best practices and recommendations
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[Figure 27: Diagram/Chart/Graph]
Remember: Ethical considerations and implications
• Assessment criteria and rubrics
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Note: Comparative analysis and synthesis
• Key terms and definitions
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Example 29: Study tips and learning strategies
• Ethical considerations and implications
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Results 4: Learning outcomes and objectives
Example 30: Current trends and future directions
• Statistical analysis and interpretation
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Practice Problem 31: Research findings and conclusions
• Literature review and discussion
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[Figure 32: Diagram/Chart/Graph]
Definition: Research findings and conclusions
• Case studies and real-world applications
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- Note: Important consideration
Note: Current trends and future directions
• Historical development and evolution
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Example 34: Assessment criteria and rubrics
• Learning outcomes and objectives
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- Example: Practical application scenario
Key Concept: Research findings and conclusions
• Case studies and real-world applications
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- Example: Practical application scenario
Definition: Case studies and real-world applications
• Historical development and evolution
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Formula: [Mathematical expression or equation]
Practice Problem 37: Theoretical framework and methodology
• Experimental procedures and results
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- Example: Practical application scenario
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Formula: [Mathematical expression or equation]
Important: Literature review and discussion
• Experimental procedures and results
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- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 39: Case studies and real-world applications
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 40: Diagram/Chart/Graph]
Abstract 5: Comparative analysis and synthesis
Important: Study tips and learning strategies
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Comparative analysis and synthesis
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 42: Learning outcomes and objectives
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 43: Historical development and evolution
• Critical analysis and evaluation
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- Note: Important consideration
Key Concept: Current trends and future directions
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Experimental procedures and results
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Key terms and definitions
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Historical development and evolution
• Current trends and future directions
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- Note: Important consideration
[Figure 48: Diagram/Chart/Graph]
Key Concept: Literature review and discussion
• Comparative analysis and synthesis
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- Example: Practical application scenario
- Note: Important consideration
Remember: Best practices and recommendations
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Review 6: Key terms and definitions
Note: Experimental procedures and results
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 51: Diagram/Chart/Graph]
Practice Problem 51: Problem-solving strategies and techniques
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Example 52: Practical applications and examples
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Best practices and recommendations
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Critical analysis and evaluation
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 55: Diagram/Chart/Graph]
Practice Problem 55: Problem-solving strategies and techniques
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Case studies and real-world applications
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 57: Diagram/Chart/Graph]
Note: Problem-solving strategies and techniques
• Experimental procedures and results
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- Example: Practical application scenario
- Note: Important consideration
[Figure 58: Diagram/Chart/Graph]
Remember: Current trends and future directions
• Literature review and discussion
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- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Interdisciplinary approaches
• Theoretical framework and methodology
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- Note: Important consideration
Chapter 7: Historical development and evolution
Example 60: Case studies and real-world applications
• Current trends and future directions
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Remember: Problem-solving strategies and techniques
• Research findings and conclusions
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- Example: Practical application scenario
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Definition: Current trends and future directions
• Comparative analysis and synthesis
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Remember: Practical applications and examples
• Best practices and recommendations
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- Note: Important consideration
[Figure 64: Diagram/Chart/Graph]
Key Concept: Research findings and conclusions
• Case studies and real-world applications
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- Example: Practical application scenario
- Note: Important consideration
Definition: Current trends and future directions
• Literature review and discussion
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- Example: Practical application scenario
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Important: Problem-solving strategies and techniques
• Best practices and recommendations
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- Note: Important consideration
Example 67: Theoretical framework and methodology
• Study tips and learning strategies
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- Note: Important consideration
Remember: Study tips and learning strategies
• Learning outcomes and objectives
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- Example: Practical application scenario
- Note: Important consideration
Remember: Research findings and conclusions
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 70: Diagram/Chart/Graph]
Section 8: Assessment criteria and rubrics
Remember: Learning outcomes and objectives
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Important: Theoretical framework and methodology
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Study tips and learning strategies
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Definition: Study tips and learning strategies
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Literature review and discussion
• Ethical considerations and implications
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Important: Historical development and evolution
• Comparative analysis and synthesis
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Formula: [Mathematical expression or equation]
Practice Problem 76: Literature review and discussion
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Problem-solving strategies and techniques
• Case studies and real-world applications
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[Figure 78: Diagram/Chart/Graph]
Important: Fundamental concepts and principles
• Practical applications and examples
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Definition: Best practices and recommendations
• Study tips and learning strategies
- Sub-point: Additional details and explanations
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- Note: Important consideration
[Figure 80: Diagram/Chart/Graph]
Practice 9: Case studies and real-world applications
Key Concept: Case studies and real-world applications
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 81: Diagram/Chart/Graph]
Key Concept: Case studies and real-world applications
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
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- Note: Important consideration
[Figure 82: Diagram/Chart/Graph]
Key Concept: Historical development and evolution
• Critical analysis and evaluation
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- Note: Important consideration
[Figure 83: Diagram/Chart/Graph]
Practice Problem 83: Comparative analysis and synthesis
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Critical analysis and evaluation
• Key terms and definitions
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- Example: Practical application scenario
- Note: Important consideration
Important: Ethical considerations and implications
• Statistical analysis and interpretation
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Practice Problem 86: Experimental procedures and results
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Problem-solving strategies and techniques
• Problem-solving strategies and techniques
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Practice Problem 88: Key terms and definitions
• Literature review and discussion
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Practice Problem 89: Practical applications and examples
• Interdisciplinary approaches
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- Note: Important consideration
Results 10: Problem-solving strategies and techniques
Example 90: Assessment criteria and rubrics
• Current trends and future directions
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- Note: Important consideration
[Figure 91: Diagram/Chart/Graph]
Key Concept: Experimental procedures and results
• Problem-solving strategies and techniques
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[Figure 92: Diagram/Chart/Graph]
Definition: Ethical considerations and implications
• Assessment criteria and rubrics
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Remember: Historical development and evolution
• Current trends and future directions
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Example 94: Problem-solving strategies and techniques
• Assessment criteria and rubrics
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- Note: Important consideration
[Figure 95: Diagram/Chart/Graph]
Example 95: Practical applications and examples
• Statistical analysis and interpretation
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- Note: Important consideration
Important: Learning outcomes and objectives
• Historical development and evolution
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- Note: Important consideration
Remember: Best practices and recommendations
• Fundamental concepts and principles
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- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Key terms and definitions
• Key terms and definitions
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Important: Practical applications and examples
• Fundamental concepts and principles
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Results 11: Ethical considerations and implications
Practice Problem 100: Assessment criteria and rubrics
• Case studies and real-world applications
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- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Example 101: Statistical analysis and interpretation
• Interdisciplinary approaches
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- Note: Important consideration
[Figure 102: Diagram/Chart/Graph]
Important: Historical development and evolution
• Problem-solving strategies and techniques
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Note: Best practices and recommendations
• Current trends and future directions
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Example 104: Theoretical framework and methodology
• Theoretical framework and methodology
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- Note: Important consideration
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Example 105: Fundamental concepts and principles
• Key terms and definitions
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- Note: Important consideration
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[Figure 106: Diagram/Chart/Graph]
Note: Assessment criteria and rubrics
• Comparative analysis and synthesis
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- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Theoretical framework and methodology
• Statistical analysis and interpretation
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Important: Research findings and conclusions
• Research findings and conclusions
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Example 109: Study tips and learning strategies
• Ethical considerations and implications
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- Note: Important consideration
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[Figure 110: Diagram/Chart/Graph]
Topic 12: Study tips and learning strategies
Remember: Fundamental concepts and principles
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Important: Study tips and learning strategies
• Critical analysis and evaluation
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- Note: Important consideration
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Key Concept: Ethical considerations and implications
• Assessment criteria and rubrics
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- Example: Practical application scenario
Practice Problem 113: Case studies and real-world applications
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Ethical considerations and implications
• Current trends and future directions
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- Example: Practical application scenario
- Note: Important consideration
Important: Problem-solving strategies and techniques
• Key terms and definitions
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Formula: [Mathematical expression or equation]
Definition: Research findings and conclusions
• Assessment criteria and rubrics
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- Note: Important consideration
Important: Experimental procedures and results
• Current trends and future directions
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Formula: [Mathematical expression or equation]
Key Concept: Fundamental concepts and principles
• Literature review and discussion
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Practice Problem 119: Fundamental concepts and principles
• Case studies and real-world applications
- Sub-point: Additional details and explanations
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- Note: Important consideration
[Figure 120: Diagram/Chart/Graph]
Quiz 13: Current trends and future directions
Note: Research findings and conclusions
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Remember: Critical analysis and evaluation
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
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- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Key terms and definitions
• Key terms and definitions
- Sub-point: Additional details and explanations
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Formula: [Mathematical expression or equation]
Practice Problem 123: Historical development and evolution
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Best practices and recommendations
• Problem-solving strategies and techniques
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- Example: Practical application scenario
- Note: Important consideration
Practice Problem 125: Literature review and discussion
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
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- Note: Important consideration
Formula: [Mathematical expression or equation]
Practice Problem 126: Case studies and real-world applications
• Critical analysis and evaluation
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- Example: Practical application scenario
- Note: Important consideration
Key Concept: Literature review and discussion
• Experimental procedures and results
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[Figure 128: Diagram/Chart/Graph]
Note: Study tips and learning strategies
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