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Medical Biostatistics
Fourth Edition
Editor-in-Chief
Shein-Chung Chow, Ph.D., Professor, Department of Biostatistics and Bioinformatics,
Duke University School of Medicine, Durham, North Carolina

Series Editors
Byron Jones, Biometrical Fellow, Statistical Methodology, Integrated Information Sciences,
Novartis Pharma AG, Basel, Switzerland
Jen-pei Liu, Professor, Division of Biometry, Department of Agronomy,
National Taiwan University, Taipei, Taiwan
Karl E. Peace, Georgia Cancer Coalition, Distinguished Cancer Scholar, Senior Research Scientist
and Professor of Biostatistics, Jiann-Ping Hsu College of Public Health,
Georgia Southern University, Statesboro, Georgia
Bruce W. Turnbull, Professor, School of Operations Research and Industrial Engineering,
Cornell University, Ithaca, New York

Published Titles
Adaptive Design Methods in Clinical
Trials, Second Edition
Shein-Chung Chow and Mark Chang
Adaptive Designs for Sequential
Treatment Allocation
Alessandro Baldi Antognini
and Alessandra Giovagnoli
Adaptive Design Theory and
Implementation Using SAS and R,
Second Edition
Mark Chang
Advanced Bayesian Methods for
Medical Test Accuracy
Lyle D. Broemeling
Analyzing Longitudinal Clinical Trial Data:
A Practical Guide
Craig Mallinckrodt and Ilya Lipkovich
Applied Biclustering Methods for Big
and High-Dimensional Data Using R
Adetayo Kasim, Ziv Shkedy,
Sebastian Kaiser, Sepp Hochreiter,
and Willem Talloen
Applied Meta-Analysis with R
Ding-Geng (Din) Chen and Karl E. Peace
Applied Surrogate Endpoint Evaluation
Methods with SAS and R
Ariel Alonso, Theophile Bigirumurame,
Tomasz Burzykowski, Marc Buyse,
Geert Molenberghs, Leacky Muchene,
Nolen Joy Perualila, Ziv Shkedy,
and Wim Van der Elst
Basic Statistics and Pharmaceutical
Statistical Applications, Second Edition
James E. De Muth
Bayesian Adaptive Methods for
Clinical Trials
Scott M. Berry, Bradley P. Carlin,
J. Jack Lee, and Peter Muller
Bayesian Analysis Made Simple:
An Excel GUI for WinBUGS
Phil Woodward
Bayesian Designs for Phase I–II
Clinical Trials
Ying Yuan, Hoang Q. Nguyen,
and Peter F. Thall
Bayesian Methods for Measures
of Agreement
Lyle D. Broemeling
Bayesian Methods for Repeated Measures
Lyle D. Broemeling
Bayesian Methods in Epidemiology
Lyle D. Broemeling
Bayesian Methods in Health Economics
Gianluca Baio
Bayesian Missing Data Problems: EM,
Data Augmentation and Noniterative
Computation
Ming T. Tan, Guo-Liang Tian,
and Kai Wang Ng
Published Titles
Bayesian Modeling in Bioinformatics
Dipak K. Dey, Samiran Ghosh,
and Bani K. Mallick
Benefit-Risk Assessment in
Pharmaceutical Research and
Development
Andreas Sashegyi, James Felli,
and Rebecca Noel
Benefit-Risk Assessment Methods in
Medical Product Development: Bridging
Qualitative and Quantitative Assessments
Qi Jiang and Weili He
Bioequivalence and Statistics in Clinical
Pharmacology, Second Edition
Scott Patterson and Byron Jones
Biosimilar Clinical Development:
Scientific Considerations and New
Methodologies
Kerry B. Barker, Sandeep M. Menon,
Ralph B. D’Agostino, Sr., Siyan Xu, and Bo Jin
Biosimilars: Design and Analysis of
Follow-on Biologics
Shein-Chung Chow
Biostatistics: A Computing Approach
Stewart J. Anderson
Cancer Clinical Trials: Current and
Controversial Issues in Design and
Analysis
Stephen L. George, Xiaofei Wang,
and Herbert Pang
Causal Analysis in Biomedicine and
Epidemiology: Based on Minimal
Sufficient Causation
Mikel Aickin
Clinical and Statistical Considerations in
Personalized Medicine
Claudio Carini, Sandeep Menon, and Mark Chang
Clinical Trial Data Analysis Using R
Ding-Geng (Din) Chen and Karl E. Peace
Clinical Trial Data Analysis Using R and SAS,
Second Edition
Ding-Geng (Din) Chen, Karl E. Peace,
and Pinggao Zhang
Clinical Trial Methodology
Karl E. Peace and Ding-Geng (Din) Chen
Clinical Trial Optimization Using R
Alex Dmitrienko and Erik Pulkstenis
Cluster Randomised Trials:
Second Edition
Richard J. Hayes and Lawrence H. Moulton
Computational Methods in Biomedical
Research
Ravindra Khattree and Dayanand N. Naik
Computational Pharmacokinetics
Anders Källén
Confidence Intervals for Proportions
and Related Measures of Effect Size
Robert G. Newcombe
Controversial Statistical Issues in
Clinical Trials
Shein-Chung Chow
Data Analysis with Competing Risks
and Intermediate States
Ronald B. Geskus
Data and Safety Monitoring Committees
in Clinical Trials, Second Edition
Jay Herson
Design and Analysis of Animal Studies
in Pharmaceutical Development
Shein-Chung Chow and Jen-pei Liu
Design and Analysis of Bioavailability
and Bioequivalence Studies, Third Edition
Shein-Chung Chow and Jen-pei Liu
Design and Analysis of Bridging Studies
Jen-pei Liu, Shein-Chung Chow,
and Chin-Fu Hsiao
Design & Analysis of Clinical Trials for
Economic Evaluation & Reimbursement:
An Applied Approach Using SAS & STATA
Iftekhar Khan
Design and Analysis of Clinical Trials
for Predictive Medicine
Shigeyuki Matsui, Marc Buyse,
and Richard Simon
Design and Analysis of Clinical Trials with
Time-to-Event Endpoints
Karl E. Peace
Design and Analysis of Non-Inferiority Trials
Mark D. Rothmann, Brian L. Wiens,
and Ivan S. F. Chan
Published Titles
Difference Equations with Public Health
Applications
Lemuel A. Moyé and Asha Seth Kapadia
DNA Methylation Microarrays:
Experimental Design and Statistical
Analysis
Sun-Chong Wang and Arturas Petronis
DNA Microarrays and Related Genomics
Techniques: Design, Analysis, and
Interpretation of Experiments
David B. Allison, Grier P. Page,
T. Mark Beasley, and Jode W. Edwards
Dose Finding by the Continual
Reassessment Method
Ying Kuen Cheung
Dynamical Biostatistical Models
Daniel Commenges and
Hélène Jacqmin-Gadda
Elementary Bayesian Biostatistics
Lemuel A. Moyé
Emerging Non-Clinical Biostatistics in
Biopharmaceutical Development and
Manufacturing
Harry Yang
Empirical Likelihood Method in
Survival Analysis
Mai Zhou
Essentials of a Successful Biostatistical
Collaboration
Arul Earnest
Exposure–Response Modeling: Methods
and Practical Implementation
Jixian Wang
Frailty Models in Survival Analysis
Andreas Wienke
Fundamental Concepts for New Clinical
Trialists
Scott Evans and Naitee Ting
Generalized Linear Models: A Bayesian
Perspective
Dipak K. Dey, Sujit K. Ghosh, and
Bani K. Mallick
Handbook of Regression and Modeling:
Applications for the Clinical and
Pharmaceutical Industries
Daryl S. Paulson
Inference Principles for Biostatisticians
Ian C. Marschner
Interval-Censored Time-to-Event Data:
Methods and Applications
Ding-Geng (Din) Chen, Jianguo Sun,
and Karl E. Peace
Introductory Adaptive Trial Designs:
A Practical Guide with R
Mark Chang
Joint Models for Longitudinal and Time-
to-Event Data: With Applications in R
Dimitris Rizopoulos
Measures of Interobserver Agreement
and Reliability, Second Edition
Mohamed M. Shoukri
Medical Biostatistics, Fourth Edition
A. Indrayan
Meta-Analysis in Medicine and
Health Policy
Dalene Stangl and Donald A. Berry
Methods in Comparative Effectiveness
Research
Constantine Gatsonis and Sally C. Morton
Mixed Effects Models for the Population
Approach: Models, Tasks, Methods
and Tools
Marc Lavielle
Modeling to Inform Infectious Disease
Control
Niels G. Becker
Modern Adaptive Randomized Clinical
Trials: Statistical and Practical Aspects
Oleksandr Sverdlov
Monte Carlo Simulation for the
Pharmaceutical Industry: Concepts,
Algorithms, and Case Studies
Mark Chang
Multiregional Clinical Trials for
Simultaneous Global New Drug
Development
Joshua Chen and Hui Quan
Multiple Testing Problems in
Pharmaceutical Statistics
Alex Dmitrienko, Ajit C. Tamhane,
and Frank Bretz
Published Titles
Noninferiority Testing in Clinical Trials:
Issues and Challenges
Tie-Hua Ng
Optimal Design for Nonlinear Response
Models
Valerii V. Fedorov and Sergei L. Leonov
Patient-Reported Outcomes:
Measurement, Implementation and
Interpretation
Joseph C. Cappelleri, Kelly H. Zou,
Andrew G. Bushmakin, Jose Ma. J. Alvir,
Demissie Alemayehu, and Tara Symonds
Quantitative Evaluation of Safety in Drug
Development: Design, Analysis and
Reporting
Qi Jiang and H. Amy Xia
Quantitative Methods for
HIV/AIDS Research
Cliburn Chan, Michael G. Hudgens, and
Shein-Chung Chow
Quantitative Methods for Traditional
Chinese Medicine Development
Shein-Chung Chow
Randomized Clinical Trials of
Nonpharmacological Treatments
Isabelle Boutron, Philippe Ravaud,
and David Moher
Randomized Phase II Cancer
Clinical Trials
Sin-Ho Jung
Repeated Measures Design with
Generalized Linear Mixed Models for
Randomized Controlled Trials
Toshiro Tango
Sample Size Calculations for Clustered
and Longitudinal Outcomes in Clinical
Research
Chul Ahn, Moonseong Heo,
and Song Zhang
Sample Size Calculations in Clinical
Research, Third Edition
Shein-Chung Chow, Jun Shao, Hansheng
Wang, and Yuliya Lokhnygina
Statistical Analysis of Human Growth
and Development
Yin Bun Cheung
Statistical Design and Analysis of Clinical
Trials: Principles and Methods
Weichung Joe Shih and Joseph Aisner
Statistical Design and Analysis of
Stability Studies
Shein-Chung Chow
Statistical Evaluation of Diagnostic
Performance: Topics in ROC Analysis
Kelly H. Zou, Aiyi Liu, Andriy Bandos,
Lucila Ohno-Machado, and Howard Rockette
Statistical Methods for Clinical Trials
Mark X. Norleans
Statistical Methods for Drug Safety
Robert D. Gibbons and Anup K. Amatya
Statistical Methods for Healthcare
Performance Monitoring
Alex Bottle and Paul Aylin
Statistical Methods for Immunogenicity
Assessment
Harry Yang, Jianchun Zhang, Binbing Yu,
and Wei Zhao
Statistical Methods in Drug Combination
Studies
Wei Zhao and Harry Yang
Statistical Testing Strategies in the
Health Sciences
Albert Vexler, Alan D. Hutson,
and Xiwei Chen
Statistics in Drug Research:
Methodologies and Recent
Developments
Shein-Chung Chow and Jun Shao
Statistics in the Pharmaceutical Industry,
Third Edition
Ralph Buncher and Jia-Yeong Tsay
Survival Analysis in Medicine and
Genetics
Jialiang Li and Shuangge Ma
Theory of Drug Development
Eric B. Holmgren
Translational Medicine: Strategies and
Statistical Methods
Dennis Cosmatos and Shein-Chung Chow
http://taylorandfrancis.com
Medical Biostatistics
Fourth Edition

Abhaya Indrayan
Rajeev Kumar Malhotra
CRC Press
Taylor & Francis Group
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Contents

Summary Tables................................................................................................................................................................................... xxix

Preface...................................................................................................................................................................................................xxxv
Frequently Used Notations............................................................................................................................................................. xxxvii

1. Medical Uncertainties.......................................................................................................................................................................1
1.1 Uncertainties in Health and Disease.....................................................................................................................................2
1.1.1 Uncertainties due to Intrinsic Variation..................................................................................................................2
1.1.1.1 Biologic Variability......................................................................................................................................2
1.1.1.2 Genetic Variability......................................................................................................................................3
1.1.1.3 Variation in Behavior and Other Host Factors........................................................................................3
1.1.1.4 Environmental Variability.........................................................................................................................3
1.1.1.5 Sampling Fluctuations................................................................................................................................3
1.1.2 Natural Variation in Assessment..............................................................................................................................4
1.1.2.1 Observer Variability....................................................................................................................................4
1.1.2.2 Variability in Treatment Strategies...........................................................................................................4
1.1.2.3 Instrument and Laboratory Variability...................................................................................................4
1.1.2.4 Imperfect Tools............................................................................................................................................4
1.1.2.5 Incomplete Information on the Patient....................................................................................................5
1.1.2.6 Poor Compliance with the Regimen.........................................................................................................5
1.1.3 Knowledge Limitations..............................................................................................................................................5
1.1.3.1 Epistemic Uncertainties..............................................................................................................................5
1.1.3.2 Chance Variability.......................................................................................................................................6
1.1.3.3 Diagnostic, Therapeutic, and Prognostic Uncertainties........................................................................6
1.1.3.4 Predictive and Other Uncertainties..........................................................................................................6
1.2 Uncertainties in Medical Research........................................................................................................................................7
1.2.1 Empiricism in Medical Research..............................................................................................................................7
1.2.1.1 Laboratory Experiments.............................................................................................................................7
1.2.1.2 Clinical Trials...............................................................................................................................................7
1.2.1.3 Surgical Procedures....................................................................................................................................7
1.2.1.4 Epidemiological Research..........................................................................................................................8
1.2.2 Elements of Minimizing the Impact of Uncertainties on Research....................................................................8
1.2.2.1 Proper Design..............................................................................................................................................8
1.2.2.2 Improved Medical Methods......................................................................................................................8
1.2.2.3 Analysis and Synthesis...............................................................................................................................9
1.3 Uncertainties in Health Planning and Evaluation..............................................................................................................9
1.3.1 Health Situation Analysis..........................................................................................................................................9
1.3.1.1 Identification of the Specifics of the Problem........................................................................................10
1.3.1.2 Magnitude of the Problem.......................................................................................................................10
1.3.1.3 Health Infrastructure...............................................................................................................................10
1.3.1.4 Feasibility of Remedial Steps...................................................................................................................11
1.3.2 Evaluation of Health Programs..............................................................................................................................11
1.4 Management of Uncertainties: About This Book..............................................................................................................11
1.4.1 Contents of the Book................................................................................................................................................12
1.4.1.1 Chapters......................................................................................................................................................12
1.4.1.2 Limitations and Strengths.......................................................................................................................13
1.4.1.3 New in the Fourth Edition.......................................................................................................................14
1.4.1.4 Unique Contribution of This Book.........................................................................................................14

ix
x Contents

1.4.2 Salient Features of the Text......................................................................................................................................15

1.4.2.1 System of Notations..................................................................................................................................15
1.4.2.2 Guide Chart of the Biostatistical Methods............................................................................................16
References..........................................................................................................................................................................................16
Exercises.............................................................................................................................................................................................16

2. Basics of Medical Studies..............................................................................................................................................................17

2.1 Study Protocol........................................................................................................................................................................17
2.1.1 Problem, Objectives, and Hypotheses...................................................................................................................17
2.1.1.1 Problem.......................................................................................................................................................17
2.1.1.2 Broad and Specific Objectives.................................................................................................................18
2.1.1.3 Hypotheses.................................................................................................................................................18
2.1.2 Protocol Content........................................................................................................................................................19
2.2 Types of Medical Studies......................................................................................................................................................21
2.2.1 Elements of a Study Design.....................................................................................................................................22
2.2.2 Basic Types of Study Design...................................................................................................................................22
2.2.2.1 Descriptive Studies...................................................................................................................................23
2.2.2.2 Analytical Studies and Their Basic Types.............................................................................................24
2.2.3 Choosing a Design....................................................................................................................................................24
2.2.3.1 Recommended Design for Particular Setups........................................................................................24
2.2.3.2 Choice of Design by Level of Evidence..................................................................................................25
2.3 Data Collection.......................................................................................................................................................................27
2.3.1 Nature of Data...........................................................................................................................................................27
2.3.1.1 Factual, Knowledge-Based, and Opinion-Based Data.........................................................................27
2.3.1.2 Method of Obtaining the Data................................................................................................................27
2.3.2 Tools of Data Collection...........................................................................................................................................28
2.3.2.1 Existing Records........................................................................................................................................28
2.3.2.2 Questionnaires and Schedules................................................................................................................28
2.3.2.3 Likert Scale.................................................................................................................................................29
2.3.2.4 Guttman Scale............................................................................................................................................30
2.3.3 Pretesting and Pilot Study.......................................................................................................................................30
2.4 Nonsampling Errors and Other Biases...............................................................................................................................31
2.4.1 Nonresponse..............................................................................................................................................................31
2.4.2 Variety of Biases to Guard Against........................................................................................................................31
2.4.2.1 List of Biases...............................................................................................................................................31
2.4.2.2 Steps for Minimizing Bias........................................................................................................................35
References..........................................................................................................................................................................................35
Exercises.............................................................................................................................................................................................36

3. Sampling Methods..........................................................................................................................................................................37
3.1 Sampling Concepts................................................................................................................................................................37
3.1.1 Advantages and Limitations of Sampling.............................................................................................................37
3.1.1.1 Sampling Fluctuations..............................................................................................................................37
3.1.1.2 Advantages of Sampling..........................................................................................................................38
3.1.1.3 Limitations of Sampling...........................................................................................................................38
3.1.2 Some Special Terms Used in Sampling.................................................................................................................38
3.1.2.1 Unit of Inquiry and Sampling Unit........................................................................................................38
3.1.2.2 Sampling Frame........................................................................................................................................39
3.1.2.3 Parameters and Statistics.........................................................................................................................39
3.1.2.4 Sample Size................................................................................................................................................39
3.1.2.5 Nonrandom and Random Sampling......................................................................................................39
3.1.2.6 Sampling Weight.......................................................................................................................................39
Contents xi

3.2 Common Methods of Random Sampling...........................................................................................................................40

3.2.1 Simple Random Sampling.......................................................................................................................................40
3.2.2 Stratified Random Sampling...................................................................................................................................41
3.2.3 Multistage Random Sampling................................................................................................................................43
3.2.4 Cluster Random Sampling......................................................................................................................................43
3.2.5 Systematic Random Sampling................................................................................................................................45
3.2.6 Choice of the Method of Random Sampling........................................................................................................46
3.3 Some Other Methods of Sampling......................................................................................................................................46
3.3.1 Other Random Methods of Sampling....................................................................................................................46
3.3.1.1 Probability Proportional to Size Sampling............................................................................................47
3.3.1.2 Area Sampling...........................................................................................................................................47
3.3.1.3 Inverse Sampling.......................................................................................................................................47
3.3.1.4 Consecutive Subjects Attending a Clinic...............................................................................................48
3.3.1.5 Sequential Sampling.................................................................................................................................48
3.3.2 Nonrandom Methods of Sampling........................................................................................................................48
3.3.2.1 Convenience Sample.................................................................................................................................48
3.3.2.2 Other Types of Purposive Samples.........................................................................................................49
References..........................................................................................................................................................................................49
Exercises.............................................................................................................................................................................................49

4. Designs for Observational Studies..............................................................................................................................................51

4.1 Some Basic Concepts.............................................................................................................................................................51
4.1.1 Antecedent and Outcome........................................................................................................................................51
4.1.2 Confounders..............................................................................................................................................................52
4.1.3 Effect Size...................................................................................................................................................................53
4.1.4 Ecological Studies.....................................................................................................................................................53
4.2 Prospective Studies................................................................................................................................................................53
4.2.1 Variations of Prospective Studies...........................................................................................................................54
4.2.1.1 Cohort Study..............................................................................................................................................54
4.2.1.2 Longitudinal Study...................................................................................................................................54
4.2.1.3 Repeated Measures Study........................................................................................................................55
4.2.2 Selection of Subjects for a Prospective Study.......................................................................................................55
4.2.2.1 Comparison Group in a Prospective Study...........................................................................................55
4.2.3 Potential Biases in Prospective Studies.................................................................................................................56
4.2.3.1 Selection Bias.............................................................................................................................................56
4.2.3.2 Bias due to Loss in Follow-Up.................................................................................................................56
4.2.3.3 Assessment Bias and Errors....................................................................................................................56
4.2.3.4 Bias due to Change in the Status............................................................................................................57
4.2.3.5 Confounding Bias.....................................................................................................................................57
4.2.3.6 Post Hoc Bias..............................................................................................................................................57
4.2.4 Merits and Demerits of Prospective Studies.........................................................................................................57
4.2.4.1 Merits of Prospective Studies..................................................................................................................57
4.2.4.2 Demerits of Prospective Studies.............................................................................................................57
4.3 Retrospective Studies............................................................................................................................................................58
4.3.1 Case–Control Design...............................................................................................................................................58
4.3.1.1 Nested Case–Control Design..................................................................................................................59
4.3.2 Selection of Cases and Controls..............................................................................................................................59
4.3.2.1 Selection of Cases......................................................................................................................................60
4.3.2.2 Selection of Controls.................................................................................................................................60
4.3.2.3 Sampling Methods in Retrospective Studies........................................................................................60
4.3.2.4 Confounders and Matching.....................................................................................................................60
4.3.3 Merits and Demerits of Case–Control Studies.....................................................................................................61
4.3.3.1 Merits of Case–Control Studies..............................................................................................................61
4.3.3.2 Demerits of Case–Control Studies..........................................................................................................61
xii Contents

4.4 Cross-Sectional Studies.........................................................................................................................................................62

4.4.1 Selection of Subjects for a Cross-Sectional Study................................................................................................62
4.4.2 Merits and Demerits of Cross-Sectional Studies..................................................................................................62
4.4.2.1 Demerits of Cross-Sectional Studies......................................................................................................62
4.4.2.2 Merits of Cross-Sectional Studies...........................................................................................................63
4.5 Comparative Performance of Prospective, Retrospective, and Cross-Sectional Studies............................................63
4.5.1 Comparative Features and Performance Comparison....................................................................................... 64
4.5.2 Reporting Results of Observational Studies: STROBE........................................................................................65
References..........................................................................................................................................................................................66
Exercises.............................................................................................................................................................................................66

5. Medical Experiments......................................................................................................................................................................67
5.1 Basic Features of Medical Experiments..............................................................................................................................67
5.1.1 Statistical Principles of Experimentation..............................................................................................................68
5.1.1.1 Control Group............................................................................................................................................68
5.1.1.2 Randomization..........................................................................................................................................68
5.1.1.3 Replication..................................................................................................................................................69
5.1.2 Advantages and Limitations of Experiments.......................................................................................................69
5.1.2.1 Advantages.................................................................................................................................................69
5.1.2.2 Limitations.................................................................................................................................................70
5.2 Design of Experiments..........................................................................................................................................................70
5.2.1 Classical Designs: One-Way, Two-Way, and Factorial.........................................................................................71
5.2.1.1 One-Way Design........................................................................................................................................71
5.2.1.2 Two-Way Design........................................................................................................................................71
5.2.1.3 Interaction..................................................................................................................................................72
5.2.1.4 K-Way and Factorial Experiments...........................................................................................................73
5.2.2 Some Common Unconventional Designs..............................................................................................................74
5.2.2.1 Repeated Measures Design......................................................................................................................74
5.2.2.2 Crossover Design......................................................................................................................................75
5.2.2.3 Other Complex Designs...........................................................................................................................76
5.3 Choice of Sampling of Units for Laboratory Experiments...............................................................................................76
5.3.1 Choice of Experimental Unit...................................................................................................................................77
5.3.2 Sampling Methods in Laboratory Experiments...................................................................................................77
5.3.3 Choosing a Design of Experiment.........................................................................................................................77
5.3.4 Pharmacokinetic Studies.........................................................................................................................................78
References..........................................................................................................................................................................................78
Exercises.............................................................................................................................................................................................79

6. Clinical Trials...................................................................................................................................................................................81
6.1 Therapeutic Trials..................................................................................................................................................................81
6.1.1 Phases of a Clinical Trial.........................................................................................................................................81
6.1.1.1 Phase I Trial................................................................................................................................................81
6.1.1.2 Phase II Trial..............................................................................................................................................82
6.1.1.3 Phase III Trial.............................................................................................................................................82
6.1.1.4 Phase IV: Postmarketing Surveillance...................................................................................................83
6.1.2 Randomized Controlled Trials: Selection of Subjects.........................................................................................83
6.1.2.1 Selection of Participants for RCT............................................................................................................83
6.1.2.2 Control Group in a Clinical Trial............................................................................................................84
6.1.3 Randomization and Matching................................................................................................................................85
6.1.3.1 Randomization..........................................................................................................................................86
6.1.3.2 Matching.....................................................................................................................................................86
6.1.4 Methods of Random Allocation.............................................................................................................................87
6.1.4.1 Allocation Out of a Large Number of Available Subjects...................................................................87
6.1.4.2 Random Allocation of Consecutive Patients Coming to a Clinic......................................................87
6.1.4.3 Block, Cluster, and Stratified Randomization.......................................................................................88
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6.1.5 Blinding and Masking.............................................................................................................................................89

6.1.5.1 Blinding......................................................................................................................................................89
6.1.5.2 Concealment of Allocation.......................................................................................................................89
6.1.5.3 Masking......................................................................................................................................................90
6.2 Issues in Clinical Trials.........................................................................................................................................................90
6.2.1 Outcome Assessment...............................................................................................................................................90
6.2.1.1 Specification of End Points or Outcome.................................................................................................90
6.2.1.2 Causal Inference........................................................................................................................................91
6.2.1.3 Side Effects.................................................................................................................................................91
6.2.1.4 Effectiveness versus Efficacy...................................................................................................................92
6.2.1.5 Pragmatic Trials.........................................................................................................................................92
6.2.2 Various Equivalences in Clinical Trials.................................................................................................................92
6.2.2.1 Superiority, Equivalence, and Noninferiority Trials............................................................................92
6.2.2.2 Therapeutic Equivalence and Bioequivalence......................................................................................93
6.2.3 Designs for Clinical Trials.......................................................................................................................................94
6.2.3.1 n-of-1, Up-and-Down, and Sequential Designs....................................................................................94
6.2.3.2 Choosing a Design for a Clinical Trial...................................................................................................95
6.2.4 Designs with Interim Appraisals...........................................................................................................................95
6.2.4.1 Designs with Provision to Stop Early.....................................................................................................96
6.2.4.2 Adaptive Designs......................................................................................................................................96
6.2.5 Biostatistical Ethics for Clinical Trials...................................................................................................................97
6.2.5.1 Equipoise....................................................................................................................................................97
6.2.5.2 Ethical Cautions.........................................................................................................................................98
6.2.5.3 Statistical Considerations in a Multicentric Trial.................................................................................98
6.2.5.4 Multiple Treatments with Different Outcomes in the Same Trial......................................................98
6.2.5.5 Size of the Trial..........................................................................................................................................99
6.2.5.6 Compliance................................................................................................................................................99
6.2.6 Reporting the Results of a Clinical Trial...............................................................................................................99
6.2.6.1 CONSORT Statement................................................................................................................................99
6.2.6.2 Registration of Trials and Open Access...............................................................................................100
6.3 Trials Other than for Therapeutics....................................................................................................................................101
6.3.1 Clinical Trials for Diagnostic and Prophylactic Modalities.............................................................................101
6.3.1.1 Diagnostic Trials......................................................................................................................................101
6.3.1.2 Prophylactic Trials in Clinics.................................................................................................................102
6.3.2 Field Trials for Screening, Prophylaxis, and Vaccines.......................................................................................102
6.3.2.1 Screening Trials.......................................................................................................................................102
6.3.2.2 Prophylactic Trials in the Field..............................................................................................................102
6.3.2.3 Vaccine Trials...........................................................................................................................................103
6.3.3 Issues in Field Trials...............................................................................................................................................103
6.3.3.1 Randomization and Blinding in Field Trials.......................................................................................103
6.3.3.2 Designs for Field Trials...........................................................................................................................104
References........................................................................................................................................................................................104
Exercises...........................................................................................................................................................................................105

7. Numerical Methods for Representing Variation....................................................................................................................107

7.1 Types of Measurement........................................................................................................................................................107
7.1.1 Nominal, Metric, and Ordinal Scales..................................................................................................................107
7.1.1.1 Nominal Scale..........................................................................................................................................107
7.1.1.2 Metric Scale..............................................................................................................................................108
7.1.1.3 Ordinal Scale............................................................................................................................................108
7.1.1.4 Grouping of a Metric Scale (Categorizing Continuous Measurements).........................................109
7.1.2 Other Classifications of the Types of Measurement.......................................................................................... 110
7.1.2.1 Discrete and Continuous Variables...................................................................................................... 110
7.1.2.2 Qualitative and Quantitative Data....................................................................................................... 111
7.1.2.3 Stochastic and Deterministic Variables............................................................................................... 111
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7.2 Tabular Presentation............................................................................................................................................................ 111

7.2.1 Contingency Tables and Frequency Distribution..............................................................................................112
7.2.1.1 Empty Cells..............................................................................................................................................113
7.2.1.2 Problems in Preparing a Contingency Table on Metric Data...........................................................113
7.2.1.3 Features of a Table...................................................................................................................................113
7.2.2 Other Types of Statistical Tables........................................................................................................................... 114
7.2.2.1 Multiple Responses Tables..................................................................................................................... 114
7.2.2.2 Statistical Tables.......................................................................................................................................115
7.2.2.3 What Is a Good Statistical Table?..........................................................................................................115
7.3 Rates and Ratios...................................................................................................................................................................115
7.3.1 Proportion, Rate, and Ratio...................................................................................................................................115
7.3.1.1 Proportion................................................................................................................................................ 116
7.3.1.2 Rate............................................................................................................................................................ 116
7.3.1.3 Ratio.......................................................................................................................................................... 116
7.4 Central and Other Locations..............................................................................................................................................117
7.4.1 Central Values: Mean, Median, and Mode..........................................................................................................117
7.4.1.1 Understanding Mean, Median, and Mode.......................................................................................... 118
7.4.1.2 Calculation in the Case of Grouped Data............................................................................................ 118
7.4.1.3 Which Central Value to Use?.................................................................................................................120
7.4.1.4 Geometric Mean......................................................................................................................................121
7.4.1.5 Harmonic Mean.......................................................................................................................................121
7.4.2 Other Locations: Quantiles...................................................................................................................................122
7.4.2.1 Quantiles in Ungrouped Data...............................................................................................................123
7.4.2.2 Quantiles in Grouped Data....................................................................................................................123
7.4.2.3 Interpretation of Quantiles....................................................................................................................124
7.5 Measuring Variability.........................................................................................................................................................125
7.5.1 Variance and Standard Deviation........................................................................................................................126
7.5.1.1 Variance and Standard Deviation in Ungrouped Data.....................................................................126
7.5.1.2 Variance and Standard Deviation in Grouped Data..........................................................................128
7.5.1.3 Variance of Sum or Difference of Two Measurements......................................................................128
7.5.1.4 Measuring Variation in Skewed and Nominal Data: Interquartile Range and Variation Ratio......... 128
7.5.2 Coefficient of Variation..........................................................................................................................................129
References........................................................................................................................................................................................131
Exercises...........................................................................................................................................................................................131

8. Presentation of Variation by Figures: Data Visualization....................................................................................................133

8.1 Graphs for Frequency Distribution...................................................................................................................................133
8.1.1 Histogram and Its Variants...................................................................................................................................134
8.1.1.1 Histogram.................................................................................................................................................134
8.1.1.2 Stem-and-Leaf Plot..................................................................................................................................134
8.1.1.3 Line Histogram and Dot Plot................................................................................................................136
8.1.2 Polygon and Its Variants........................................................................................................................................136
8.1.2.1 Frequency Polygon..................................................................................................................................136
8.1.2.2 Area Diagram..........................................................................................................................................136
8.1.3 Frequency Curve.....................................................................................................................................................136
8.2 Pie, Bar, and Line Diagrams...............................................................................................................................................136
8.2.1 Pie Diagram.............................................................................................................................................................137
8.2.1.1 Useful Features of a Pie Diagram.........................................................................................................138
8.2.1.2 Donut Diagram........................................................................................................................................138
8.2.2 Bar Diagram.............................................................................................................................................................138
8.2.3 Scatter and Line Diagrams....................................................................................................................................140
8.2.3.1 Scatter Diagram.......................................................................................................................................140
8.2.3.2 Bubble Chart............................................................................................................................................140
8.2.3.3 Line Diagram...........................................................................................................................................142
8.2.3.4 Complex Line Diagram..........................................................................................................................142
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8.2.4 Choice and Cautions in Visual Display of Data.................................................................................................143

8.2.5 Mixed and Three-Dimensional Diagrams..........................................................................................................144
8.2.5.1 Mixed Diagram........................................................................................................................................144
8.2.5.2 Box-and-Whiskers Plot...........................................................................................................................144
8.2.5.3 Three-Dimensional Diagram................................................................................................................145
8.2.5.4 Biplot.........................................................................................................................................................146
8.2.5.5 Nomogram...............................................................................................................................................146
8.3 Special Diagrams in Health and Medicine......................................................................................................................146
8.3.1 Diagrams Used in Public Health..........................................................................................................................147
8.3.1.1 Epidemic Curve.......................................................................................................................................148
8.3.1.2 Lexis Diagram..........................................................................................................................................148
8.3.2 Diagrams Used in Individual Care and Research.............................................................................................148
8.3.2.1 Growth Chart...........................................................................................................................................148
8.3.2.2 Partogram.................................................................................................................................................150
8.3.2.3 Dendrogram.............................................................................................................................................150
8.3.2.4 Radar Graph.............................................................................................................................................150
8.4 Charts and Maps..................................................................................................................................................................152
8.4.1 Charts.......................................................................................................................................................................152
8.4.1.1 Schematic Chart......................................................................................................................................152
8.4.1.2 Health Infographics................................................................................................................................152
8.4.1.3 Pedigree Chart.........................................................................................................................................153
8.4.2 Maps.........................................................................................................................................................................154
8.4.2.1 Spot Map...................................................................................................................................................154
8.4.2.2 Thematic Choroplethic Map..................................................................................................................154
8.4.2.3 Cartogram................................................................................................................................................154
References........................................................................................................................................................................................156
Exercises...........................................................................................................................................................................................156

9. Some Quantitative Aspects of Medicine..................................................................................................................................159

9.1 Some Epidemiological Measures of Health and Disease...............................................................................................159
9.1.1 Epidemiological Indicators of Neonatal Health.................................................................................................160
9.1.1.1 Birth Weight.............................................................................................................................................160
9.1.1.2 Apgar Score.............................................................................................................................................. 161
9.1.2 Epidemiological Indicators of Growth in Children........................................................................................... 161
9.1.2.1 Weight-for-Age, Height-for-Age, and Weight-for-Height.................................................................. 161
9.1.2.2 Z-Scores and Percent of Median...........................................................................................................162
9.1.2.3 T-Score.......................................................................................................................................................163
9.1.2.4 Growth Velocity.......................................................................................................................................163
9.1.2.5 Skinfold Thickness..................................................................................................................................164
9.1.2.6 Other Indicators of Growth...................................................................................................................164
9.1.3 Epidemiological Indicators of Adolescent Health..............................................................................................164
9.1.3.1 Growth in Height and Weight in Adolescence...................................................................................164
9.1.3.2 Sexual Maturity Rating..........................................................................................................................165
9.1.4 Epidemiological Indicators of Adult Health.......................................................................................................165
9.1.4.1 Obesity......................................................................................................................................................165
9.1.4.2 Smoking....................................................................................................................................................166
9.1.4.3 Physiological Functions..........................................................................................................................168
9.1.4.4 Quality of Life..........................................................................................................................................168
9.1.5 Epidemiological Indicators of Geriatric Health..................................................................................................169
9.1.5.1 Activities of Daily Living.......................................................................................................................169
9.1.5.2 Mental Health of the Elderly.................................................................................................................169
9.2 Reference Values..................................................................................................................................................................169
9.2.1 Gaussian and Other Distributions.......................................................................................................................169
9.2.1.1 Properties of a Gaussian Distribution..................................................................................................170
9.2.1.2 Other Distributions.................................................................................................................................171
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9.2.1.3 Checking Gaussianity: Simple but Approximate Methods..............................................................172

9.2.2 Reference or Normal Values.................................................................................................................................. 174
9.2.2.1 Implications of Normal Values.............................................................................................................. 174
9.2.3 Normal Range.........................................................................................................................................................175
9.2.3.1 Disease Threshold...................................................................................................................................175
9.2.3.2 Clinical Threshold...................................................................................................................................175
9.2.3.3 Statistical Threshold...............................................................................................................................176
9.3 Measurement of Uncertainty: Probability........................................................................................................................177
9.3.1 Elementary Laws of Probability...........................................................................................................................177
9.3.1.1 Law of Multiplication.............................................................................................................................178
9.3.1.2 Law of Addition.......................................................................................................................................178
9.3.2 Probability in Clinical Assessments....................................................................................................................179
9.3.2.1 Probabilities in Diagnosis......................................................................................................................179
9.3.2.2 Forwarding Diagnosis............................................................................................................................180
9.3.2.3 Assessment of Prognosis........................................................................................................................180
9.3.2.4 Choice of Treatment................................................................................................................................181
9.3.3 Further on Diagnosis: Bayes’ Rule.......................................................................................................................181
9.3.3.1 Bayes’ Rule...............................................................................................................................................181
9.3.3.2 Extension of Bayes’ Rule.........................................................................................................................182
9.4 Validity of Medical Tests.....................................................................................................................................................183
9.4.1 Sensitivity and Specificity.....................................................................................................................................184
9.4.1.1 Features of Sensitivity and Specificity.................................................................................................185
9.4.1.2 Likelihood Ratio......................................................................................................................................186
9.4.2 Predictivities............................................................................................................................................................186
9.4.2.1 Positive and Negative Predictivity.......................................................................................................186
9.4.2.2 Predictivity and Prevalence...................................................................................................................187
9.4.2.3 Meaning of Prevalence for Predictivity...............................................................................................188
9.4.2.4 Features of Positive and Negative Predictivities................................................................................189
9.4.3 Combination of Tests..............................................................................................................................................190
9.4.3.1 Tests in Series...........................................................................................................................................190
9.4.3.2 Tests in Parallel........................................................................................................................................190
9.4.4 Gains from a Test....................................................................................................................................................191
9.4.4.1 When Can a Test Be Avoided?...............................................................................................................192
9.5 Search for the Best Threshold of a Continuous Test: ROC Curve.................................................................................192
9.5.1 Sensitivity–Specificity-Based ROC Curve...........................................................................................................192
9.5.1.1 Methods to Find the Optimal Threshold Point..................................................................................194
9.5.1.2 Area under the ROC Curve...................................................................................................................195
9.5.2 Predictivity-Based ROC Curve.............................................................................................................................197
References........................................................................................................................................................................................198
Exercises...........................................................................................................................................................................................199

10. Clinimetrics and Evidence-Based Medicine............................................................................................................................203

10.1 Indicators, Indices, and Scores...........................................................................................................................................203
10.1.1 Indicators..................................................................................................................................................................203
10.1.1.1 Merits and Demerits of Indicators........................................................................................................203
10.1.1.2 Choice of Indicators................................................................................................................................204
10.1.2 Indices.......................................................................................................................................................................204
10.1.3 Scores........................................................................................................................................................................204
10.1.3.1 Scoring System for Diagnosis................................................................................................................205
10.1.3.2 Scoring for Gradation of Severity.........................................................................................................206
10.1.3.3 APACHE Scores.......................................................................................................................................207
10.2 Clinimetrics..........................................................................................................................................................................208
10.2.1 Method of Scoring..................................................................................................................................................208
10.2.1.1 Method of Scoring for Graded Characteristics...................................................................................208
10.2.1.2 Method of Scoring for Diagnosis..........................................................................................................209
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10.2.1.3 Regression Method for Scoring.............................................................................................................209

10.2.2 Validity and Reliability of a Scoring System......................................................................................................210
10.2.2.1 Validity of a Scoring System..................................................................................................................210
10.2.2.2 Reliability of a Scoring System..............................................................................................................211
10.3 Evidence-Based Medicine...................................................................................................................................................212
10.3.1 Decision Analysis...................................................................................................................................................212
10.3.1.1 Decision Tree............................................................................................................................................212
10.3.2 Other Statistical Tools for Evidence-Based Medicine........................................................................................213
10.3.2.1 Etiology Diagram....................................................................................................................................213
10.3.2.2 Expert System.......................................................................................................................................... 214
References........................................................................................................................................................................................215
Exercises...........................................................................................................................................................................................216

11. Measurement of Community Health........................................................................................................................................219

11.1 Measures of Fertility and Medical Demography............................................................................................................219
11.1.1 Indicators of Fertility..............................................................................................................................................219
11.1.2 Medical Demography.............................................................................................................................................221
11.1.2.1 Population Pyramid................................................................................................................................221
11.1.2.2 Demographic Cycle.................................................................................................................................222
11.1.2.3 Other Demographic Indicators.............................................................................................................223
11.1.2.4 Stable and Stationary Population..........................................................................................................223
11.1.2.5 Sex Ratio...................................................................................................................................................223
11.2 Indicators of Mortality........................................................................................................................................................224
11.2.1 Crude and Standardized Death Rates.................................................................................................................224
11.2.1.1 Crude Death Rate....................................................................................................................................224
11.2.1.2 Age-Specific Death Rate.........................................................................................................................224
11.2.1.3 Standardized Death Rate.......................................................................................................................224
11.2.1.4 Comparative Mortality Ratio.................................................................................................................227
11.2.2 Specific Mortality Rates.........................................................................................................................................228
11.2.2.1 Fetal Deaths and Mortality in Children..............................................................................................228
11.2.2.2 Maternal Mortality..................................................................................................................................230
11.2.2.3 Adult Mortality........................................................................................................................................230
11.2.2.4 Other Measures of Mortality.................................................................................................................231
11.2.3 Death Spectrum......................................................................................................................................................231
11.3 Measures of Morbidity........................................................................................................................................................232
11.3.1 Prevalence and Incidence......................................................................................................................................232
11.3.1.1 Point Prevalence......................................................................................................................................232
11.3.1.2 Period Prevalence....................................................................................................................................233
11.3.1.3 Prevalence Rate Ratio.............................................................................................................................233
11.3.1.4 Incidence...................................................................................................................................................233
11.3.1.5 Concept of Person-Time..........................................................................................................................234
11.3.1.6 Capture–Recapture Methodology........................................................................................................234
11.3.2 Duration of Morbidity............................................................................................................................................235
11.3.2.1 Prevalence in Relation to Duration of Morbidity...............................................................................236
11.3.2.2 Incidence from Prevalence.....................................................................................................................236
11.3.2.3 Epidemiologically Consistent Estimates..............................................................................................237
11.3.3 Morbidity Measures for Acute Conditions.........................................................................................................237
11.3.3.1 Attack Rates.............................................................................................................................................238
11.3.3.2 Disease Spectrum....................................................................................................................................238
11.4 Indicators of Social and Mental Health............................................................................................................................240
11.4.1 Indicators of Social Health....................................................................................................................................240
11.4.1.1 Education..................................................................................................................................................240
11.4.1.2 Income.......................................................................................................................................................241
11.4.1.3 Occupation...............................................................................................................................................241
11.4.1.4 Socioeconomic Status.............................................................................................................................241
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11.4.1.5 Dependency Ratio...................................................................................................................................242

11.4.1.6 Dietary Assessment................................................................................................................................242
11.4.1.7 Health Inequality....................................................................................................................................242
11.4.2 Indicators of Health Resources.............................................................................................................................243
11.4.2.1 Health Infrastructure.............................................................................................................................243
11.4.2.2 Health Expenditure................................................................................................................................244
11.4.3 Indicators of Lack of Mental Health.....................................................................................................................245
11.4.3.1 Smoking and Other Addictions............................................................................................................245
11.4.3.2 Divorces....................................................................................................................................................245
11.4.3.3 Vehicular Accidents and Crimes..........................................................................................................245
11.4.3.4 Other Measures of Lack of Mental Health..........................................................................................245
11.5 Composite Indices of Health..............................................................................................................................................246
11.5.1 Indices of Status of Comprehensive Health........................................................................................................246
11.5.1.1 Human Development Index..................................................................................................................246
11.5.1.2 Physical Quality of Life Index...............................................................................................................247
11.5.1.3 Index of Happiness.................................................................................................................................247
11.5.2 Indices of (Physical) Health Gap...........................................................................................................................248
11.5.2.1 DALYs Lost...............................................................................................................................................248
11.5.2.2 Human Poverty Index............................................................................................................................249
11.5.2.3 Index of Need for Health Resources.....................................................................................................249
References........................................................................................................................................................................................249
Exercises...........................................................................................................................................................................................250

12. Confidence Intervals, Principles of Tests of Significance, and Sample Size.....................................................................255

12.1 Sampling Distributions.......................................................................................................................................................255
12.1.1 Basic Concepts.........................................................................................................................................................255
12.1.1.1 Sampling Error........................................................................................................................................256
12.1.1.2 Point Estimate..........................................................................................................................................256
12.1.1.3 Standard Error of p and x......................................................................................................................256
12.1.2 Sampling Distribution of p and x.........................................................................................................................258
12.1.2.1 Gaussian Conditions...............................................................................................................................258
12.1.3 Obtaining Probabilities from a Gaussian Distribution.....................................................................................259
12.1.3.1 Gaussian Probability...............................................................................................................................259
12.1.3.2 Continuity Correction............................................................................................................................261
12.1.3.3 Probabilities Relating to the Mean and the Proportion.....................................................................261
12.1.4 Case of σ Not Known (t-Distribution)..................................................................................................................262
12.2 Confidence Intervals............................................................................................................................................................262
12.2.1 Confidence Interval for π, μ, and Median: Gaussian Conditions.....................................................................263
12.2.1.1 Confidence Interval for Proportion π (Large n)..................................................................................263
12.2.1.2 Lower and Upper Bounds for π (Large n)............................................................................................265
12.2.1.3 Confidence Interval for Mean μ (Large n)............................................................................................265
12.2.1.4 Confidence Bounds for Mean μ (Large n)............................................................................................267
12.2.1.5 CI for Median (Gaussian Distribution)................................................................................................268
12.2.2 Confidence Interval for Differences (Large n)....................................................................................................269
12.2.2.1 CI for the Difference in Two Independent Samples...........................................................................269
12.2.2.2 Paired Samples........................................................................................................................................270
12.2.3 Confidence Interval for π, μ, and Median: Non-Gaussian Conditions............................................................271
12.2.3.1 Confidence Interval for π (Small n).......................................................................................................272
12.2.3.2 Confidence Bound for π When the Success or Failure Rate in the Sample Is 0%..........................273
12.2.3.3 Confidence Interval for Median: Non-Gaussian Conditions............................................................274
12.3 P-Values and Statistical Significance.................................................................................................................................276
12.3.1 What Is Statistical Significance?...........................................................................................................................276
12.3.1.1 Court Judgment.......................................................................................................................................277
12.3.1.2 Errors in Diagnosis.................................................................................................................................277
12.3.1.3 Null Hypothesis......................................................................................................................................277
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12.3.1.4 Philosophical Basis of Statistical Tests.................................................................................................278

12.3.1.5 Alternative Hypothesis..........................................................................................................................278
12.3.1.6 One-Sided Alternatives: Which Tail Is Wagging?..............................................................................278
12.3.2 Errors, P-Values, and Power..................................................................................................................................279
12.3.2.1 Type I Error..............................................................................................................................................279
12.3.2.2 Type II Error.............................................................................................................................................280
12.3.2.3 Power.........................................................................................................................................................280
12.3.3 General Procedure to Obtain the P-Value...........................................................................................................281
12.3.3.1 Steps to Obtain a P-Value.......................................................................................................................281
12.3.3.2 Subtleties of Statistical Significance.....................................................................................................283
12.4 Assessing Gaussian Pattern................................................................................................................................................284
12.4.1 Approximate Methods for Assessing Gaussianity............................................................................................284
12.4.2 Significance Tests for Assessing Gaussianity.....................................................................................................285
12.4.2.1 Statistical Tests.........................................................................................................................................285
12.4.2.2 Transformations to Achieve Gaussianity............................................................................................285
12.5 Initial Debate on Statistical Significance..........................................................................................................................286
12.5.1 Confidence Interval versus Test of H0..................................................................................................................286
12.5.1.1 Equivalence of CI with Test of H0.........................................................................................................286
12.5.1.2 Valid Application of Test of Hypothesis..............................................................................................287
12.5.2 Medical Significance versus Statistical Significance..........................................................................................287
12.6 Sample Size Determination in Some Cases......................................................................................................................289
12.6.1 Sample Size Required in Estimation Setup........................................................................................................289
12.6.1.1 General Considerations for Sample Size in Estimation Setup..........................................................289
12.6.1.2 General Procedure for Determining the Sample Size for Estimation.............................................291
12.6.1.3 Formulas for Sample Size Calculation for Estimation in Simple Situations..................................292
12.6.2 Sample Size for Testing a Hypothesis with Specified Power...........................................................................294
12.6.2.1 General Considerations for Sample Size in a Testing of Hypothesis Setup...................................294
12.6.2.2 Power Calculations.................................................................................................................................295
12.6.2.3 Sample Size Formulas for Test of Hypothesis in Simple Situations................................................295
12.6.2.4 Sample Size in Some Other Popular Setups........................................................................................298
12.6.2.5 Nomograms and Tables of Sample Size...............................................................................................299
12.6.2.6 Thumb Rules............................................................................................................................................299
12.6.2.7 Power Analysis....................................................................................................................................... 300
12.6.3 Sample Size in Adaptive Clinical Trials............................................................................................................. 300
12.6.3.1 Stopping Rules in Case of Early Evidence of Success or Failure: Lan–deMets Procedure...........301
12.6.3.2 Sample Size Reestimation in Adaptive Designs.................................................................................302
References........................................................................................................................................................................................303
Exercises...........................................................................................................................................................................................304

13. Inference from Proportions.........................................................................................................................................................307

13.1 One Qualitative Variable.....................................................................................................................................................307
13.1.1 Dichotomous Categories: Binomial Distribution...............................................................................................307
13.1.1.1 Binomial Distribution.............................................................................................................................308
13.1.1.2 Large n: Gaussian Approximation to Binomial..................................................................................309
13.1.1.3 Z-Test for Proportion in One Group.....................................................................................................310
13.1.2 Poisson Distribution...............................................................................................................................................310
13.1.3 Polytomous Categories (Large n): Goodness-of-Fit Test.................................................................................... 311
13.1.3.1 Chi-Square and Its Explanation............................................................................................................312
13.1.3.2 Degrees of Freedom................................................................................................................................313
13.1.3.3 Cautions in Using Chi-Square...............................................................................................................313
13.1.3.4 Further Analysis: Partitioning of Tables.............................................................................................. 314
13.1.4 Goodness of Fit to Assess Gaussianity................................................................................................................315
13.1.5 Polytomous Categories (Small n): Exact Multinomial Test............................................................................... 316
13.1.5.1 Goodness of Fit in Small Samples......................................................................................................... 316
13.1.5.2 Data with Rare Outcomes: Negative Binomial Distribution............................................................317
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13.2 Proportions in 2×2 Tables....................................................................................................................................................318

13.2.1 Structure of 2×2 Table in Different Types of Study............................................................................................318
13.2.1.1 Structure in Prospective Study.............................................................................................................318
13.2.1.2 Structure in Retrospective Study..........................................................................................................318
13.2.1.3 Structure in Cross-Sectional Study......................................................................................................319
13.2.2 Two Independent Samples (Large n): Chi-Square Test and Proportion Test in a 2×2 Table........................319
13.2.2.1 Chi-Square Test for a 2×2 Table.............................................................................................................319
13.2.2.2 Yates’ Correction for Continuity...........................................................................................................320
13.2.2.3 Z-Test for Difference in Proportions in Two Independent Groups..................................................320
13.2.2.4 Detecting a Medically Important Difference in Proportions...........................................................321
13.2.2.5 Crossover Design with Binary Response (Large n)...........................................................................322
13.2.3 Equivalence Tests....................................................................................................................................................323
13.2.3.1 Superiority, Equivalence, and Noninferiority.....................................................................................323
13.2.3.2 Testing Equivalence................................................................................................................................324
13.2.3.3 Determining Noninferiority Margin...................................................................................................326
13.2.4 Two Independent Samples (Small n): Fisher Exact Test.....................................................................................326
13.2.4.1 Fisher Exact Test......................................................................................................................................326
13.2.4.2 Crossover Design (Small n)....................................................................................................................327
13.2.5 Proportions in Matched Pairs: McNemar Test (Large n) and Exact Test (Small n).......................................328
13.2.5.1 Large n: McNemar Test..........................................................................................................................328
13.2.5.2 Small n: Exact Test (Matched Pairs)......................................................................................................329
13.2.5.3 Comparison of Two Tests for Sensitivity and Specificity: Paired Setup.........................................330
13.3 Analysis of R×C Tables (Large n).......................................................................................................................................331
13.3.1 One Dichotomous and the Other Polytomous Variable (2×C Table)...............................................................331
13.3.1.1 Test Criterion for Association in R×C Tables.......................................................................................332
13.3.1.2 Trend in Proportions in Ordinal Categories.......................................................................................332
13.3.1.3 Dichotomy in Repeated Measures: Cochran Q-Test (Large n)..........................................................334
13.3.2 Two Polytomous Variables.....................................................................................................................................335
13.3.2.1 Chi-Square Test for Large n...................................................................................................................336
13.3.2.2 Matched Pairs: I×I Table and McNemar–Bowker Test.......................................................................337
13.4 Three-Way Tables.................................................................................................................................................................337
13.4.1 Assessment of Association in Three-Way Tables...............................................................................................338
13.4.2 Log-Linear Models..................................................................................................................................................340
13.4.2.1 Log-Linear Model for Two-Way Tables................................................................................................341
13.4.2.2 Log-Linear Model for Three-Way Tables.............................................................................................341
References........................................................................................................................................................................................343
Exercises...........................................................................................................................................................................................343

14. Relative Risk and Odds Ratio.....................................................................................................................................................347

14.1 Relative and Attributable Risks (Large n)........................................................................................................................347
14.1.1 Risk, Hazard, and Odds.........................................................................................................................................347
14.1.1.1 Risk............................................................................................................................................................347
14.1.1.2 Hazard Rate.............................................................................................................................................348
14.1.1.3 Odds..........................................................................................................................................................348
14.1.1.4 Ratios of Risks and Odds.......................................................................................................................348
14.1.2 Relative Risk............................................................................................................................................................348
14.1.2.1 RR in Independent Samples..................................................................................................................348
14.1.2.2 Confidence Interval for RR (Independent Samples)..........................................................................351
14.1.2.3 Test of Hypothesis on RR (Independent Samples).............................................................................352
14.1.2.4 RR in the Case of Matched Pairs...........................................................................................................353
14.1.3 Attributable Risk.....................................................................................................................................................353
14.1.3.1 AR in Independent Samples..................................................................................................................353
14.1.3.2 AR in Matched Pairs...............................................................................................................................354
14.1.3.3 Number Needed to Treat.......................................................................................................................355
Contents xxi

14.1.3.4 Risk Reduction.........................................................................................................................................356

14.1.3.5 Population Attributable Risk.................................................................................................................357
14.2 Odds Ratio.............................................................................................................................................................................357
14.2.1 OR in Two Independent Samples.........................................................................................................................358
14.2.1.1 Interpretation of OR................................................................................................................................358
14.2.1.2 CI for OR (Independent Samples).........................................................................................................360
14.2.1.3 Test of Hypothesis on OR (Independent Samples).............................................................................360
14.2.2 OR in Matched Pairs...............................................................................................................................................361
14.2.2.1 Confidence Interval for OR (Matched Pairs).......................................................................................362
14.2.2.2 Test of Hypothesis on OR (Matched Pairs)..........................................................................................362
14.2.2.3 Multiple Controls....................................................................................................................................363
14.3 Stratified Analysis, Sample Size, and Meta-Analysis.....................................................................................................364
14.3.1 Mantel–Haenszel Procedure.................................................................................................................................364
14.3.1.1 Pooled Relative Risk................................................................................................................................364
14.3.1.2 Pooled Odds Ratio and Chi-Square......................................................................................................365
14.3.2 Sample Size Requirement for Statistical Inference on RR and OR..................................................................366
14.3.3 Meta-Analysis..........................................................................................................................................................370
14.3.3.1 Forest Plot.................................................................................................................................................370
14.3.3.2 Validity of Meta-Analysis......................................................................................................................371
References........................................................................................................................................................................................372
Exercises...........................................................................................................................................................................................372

15. Inference from Means..................................................................................................................................................................377

15.1 Comparison of Means in One and Two Groups (Gaussian Conditions): Student t-Test............................................378
15.1.1 Comparison with a Prespecified Mean...............................................................................................................378
15.1.1.1 Student t-Test for One Sample...............................................................................................................378
15.1.2 Difference in Means in Two Samples...................................................................................................................379
15.1.2.1 Paired Samples Setup.............................................................................................................................380
15.1.2.2 Unpaired (Independent) Samples Setup..............................................................................................380
15.1.2.3 Some Features of Student t....................................................................................................................382
15.1.2.4 Effect of Unequal n..................................................................................................................................383
15.1.2.5 Difference-in-Differences Approach....................................................................................................383
15.1.3 Analysis of Crossover Designs.............................................................................................................................383
15.1.3.1 Test for Group Effect...............................................................................................................................384
15.1.3.2 Test for Carryover Effect........................................................................................................................385
15.1.3.3 Test for Treatment Effect........................................................................................................................385
15.1.4 Analysis of Data of Up-and-Down Trials............................................................................................................386
15.2 Comparison of Means in 3 or More Groups (Gaussian Conditions): ANOVA F-Test................................................387
15.2.1 One-Way ANOVA...................................................................................................................................................387
15.2.1.1 Procedure to Test H0...............................................................................................................................388
15.2.1.2 Checking the Validity of the Assumptions of ANOVA.....................................................................391
15.2.2 Two-Way ANOVA...................................................................................................................................................392
15.2.2.1 Two-Factor Design..................................................................................................................................392
15.2.2.2 Hypotheses and Their Test in Two-Way ANOVA..............................................................................393
15.2.2.3 Main Effect and Interaction (Effect).....................................................................................................395
15.2.2.4 Type I, Type II, and Type III Sums of Squares....................................................................................396
15.2.3 Repeated Measures.................................................................................................................................................397
15.2.3.1 Random Effects versus Fixed Effects and Mixed Models.................................................................397
15.2.3.2 Sphericity and Huynh–Feldt Correction.............................................................................................397
15.2.4 Multiple Comparisons: Bonferroni, Tukey, and Dunnett Tests.......................................................................398
15.2.4.1 Bonferroni Procedure.............................................................................................................................399
15.2.4.2 Tukey Test.................................................................................................................................................399
15.2.4.3 Dunnett Test............................................................................................................................................ 400
15.2.4.4 Intricacies of Multiple Comparisons................................................................................................... 400
xxii Contents

15.3 Non-Gaussian Conditions: Nonparametric Tests for Location.....................................................................................401

15.3.1 Comparison of Two Groups: Wilcoxon Tests......................................................................................................401
15.3.1.1 Case I: Paired Data—Sign Test and Wilcoxon Signed-Rank Test.....................................................401
15.3.1.2 Case II: Independent Samples—Wilcoxon Rank-Sum Test...............................................................404
15.3.2 Comparison of Three or More Groups: Kruskal–Wallis Test...........................................................................406
15.3.3 Two-Way Layout with n = 1: Friedman Test for Repeated Samples................................................................407
15.4 When Significant Is Not Significant..................................................................................................................................410
15.4.1 Nature of Statistical Significance..........................................................................................................................410
15.4.2 Testing for the Presence of a Medically Important Difference in Means.......................................................413
15.4.2.1 Detecting Specified Difference in Mean.............................................................................................. 414
15.4.2.2 Equivalence Tests for Means.................................................................................................................415
15.4.3 Power and Level of Significance...........................................................................................................................415
15.4.3.1 Further Explanation of Statistical Power.............................................................................................415
15.4.3.2 Balancing Type I and Type II Error......................................................................................................417
References........................................................................................................................................................................................418
Exercises...........................................................................................................................................................................................418

16. Relationships: Quantitative Outcome.......................................................................................................................................423

16.1 Some General Features of a Regression Setup.................................................................................................................424
16.1.1 Dependent and Independent Variables...............................................................................................................425
16.1.1.1 Simple, Multiple, and Multivariate Regressions.................................................................................425
16.1.2 Linear, Curvilinear, and Nonlinear Regressions...............................................................................................425
16.1.2.1 Linear Regression....................................................................................................................................425
16.1.2.2 Curvilinear Regression...........................................................................................................................426
16.1.2.3 Nonlinear Regressions...........................................................................................................................427
16.1.2.4 Regression through Origin....................................................................................................................428
16.1.3 Concept of Residuals..............................................................................................................................................428
16.1.4 General Method of Fitting a Regression..............................................................................................................429
16.1.5 Selection of Regressors...........................................................................................................................................430
16.1.5.1 Multicollinearity......................................................................................................................................431
16.1.5.2 Statistical Significance: Stepwise Procedures.....................................................................................431
16.1.5.3 Other Considerations..............................................................................................................................432
16.2 Linear Regression Models..................................................................................................................................................432
16.2.1 Simple Linear Regression......................................................................................................................................433
16.2.1.1 Meaning of Intercept and Slope in Simple Linear Regression.........................................................434
16.2.1.2 Estimation of Parameters of Simple Linear Regression....................................................................434
16.2.1.3 Confidence Intervals for the Parameters of Simple Linear Regression...........................................435
16.2.1.4 Tests of Hypothesis for the Parameters of Simple Linear Regression.............................................436
16.2.1.5 Confidence Band for Simple Linear Regression.................................................................................437
16.2.2 Multiple Linear Regression...................................................................................................................................438
16.2.2.1 Elements of Multiple Linear Regression..............................................................................................438
16.2.2.2 Understanding Multiple Linear Regression........................................................................................439
16.2.2.3 CI and Tests in Multiple Linear Regression....................................................................................... 440
16.3 Adequacy of a Regression.................................................................................................................................................. 440
16.3.1 Goodness of Fit and η2.......................................................................................................................................... 440
16.3.2 Multiple Correlation in Multiple Linear Regression........................................................................................ 440
16.3.3 Statistical Significance of Individual Regression Coefficients.........................................................................441
16.3.4 Validity of Assumptions....................................................................................................................................... 442
16.3.5 Choice of the Form of Regression........................................................................................................................ 443
16.3.6 Outliers and Missing Values................................................................................................................................ 446
16.4 Some Issues in Linear Regression.................................................................................................................................... 446
16.4.1 Implications of Regression....................................................................................................................................447
16.4.1.1 Standardized Coefficients......................................................................................................................447
16.4.1.2 Other Implications of Regression Models...........................................................................................447
Contents xxiii

16.4.1.3 Equality of Two Regression Lines........................................................................................................ 448

16.4.1.4 Difference-in-Differences Approach with Regression...................................................................... 448
16.4.2 Some Variations of Regression..............................................................................................................................449
16.4.2.1 Ridge Regression.....................................................................................................................................449
16.4.2.2 Multilevel Regression.............................................................................................................................449
16.4.2.3 Regression Splines..................................................................................................................................450
16.4.2.4 Analysis of Covariance...........................................................................................................................451
16.4.2.5 Some Generalizations.............................................................................................................................452
16.5 Measuring the Strength of Quantitative Relationship...................................................................................................452
16.5.1 Product–Moment and Related Correlations.......................................................................................................452
16.5.1.1 Product–Moment Correlation................................................................................................................452
16.5.1.2 Statistical Significance of r.....................................................................................................................455
16.5.1.3 Comparison of Correlations in Two Independent Samples..............................................................456
16.5.1.4 Serial Correlation....................................................................................................................................456
16.5.1.5 Partial Correlation...................................................................................................................................456
16.5.2 Rank Correlation.....................................................................................................................................................457
16.5.2.1 Spearman Rho.........................................................................................................................................457
16.5.3 Intraclass Correlation.............................................................................................................................................458
16.5.3.1 Computation of Intraclass Correlation.................................................................................................459
16.5.3.2 ANOVA Formulation and Testing the Statistical Significance of ICC.............................................459
16.6 Assessment of Quantitative Agreement...........................................................................................................................460
16.6.1 Agreement in Quantitative Measurements........................................................................................................460
16.6.1.1 Statistical Formulation of the Problem of Agreement.......................................................................460
16.6.1.2 Limits of Disagreement Approach.......................................................................................................461
16.6.1.3 Intraclass Correlation as a Measure of Agreement............................................................................462
16.6.1.4 Relative Merits of the Two Methods.....................................................................................................462
16.6.2 Alternative Methods for Assessment of Agreement.........................................................................................463
16.6.2.1 Alternative Simple Approach to Agreement Assessment.................................................................463
16.6.2.2 Agreement Assessment for Different Measurements........................................................................464
References........................................................................................................................................................................................464
Exercises...........................................................................................................................................................................................465

17. Relationships: Qualitative Dependent......................................................................................................................................469

17.1 Binary Dependent: Logistic Regression (Large n)...........................................................................................................469
17.1.1 Meaning of a Logistic Model................................................................................................................................470
17.1.1.1 Logit and Logistic Coefficients..............................................................................................................470
17.1.1.2 Logistic versus Quantitative Regression.............................................................................................470
17.1.1.3 Etiological Specification of a Logistic Model......................................................................................472
17.1.2 Assessing the Overall Adequacy of a Logistic Regression...............................................................................472
17.1.2.1 Log-Likelihood........................................................................................................................................472
17.1.2.2 Classification Accuracy..........................................................................................................................474
17.1.2.3 Hosmer–Lemeshow Test........................................................................................................................474
17.1.2.4 Other Methods of Assessing the Adequacy of a Logistic Regression.............................................475
17.2 Inference from Logistic Coefficients.................................................................................................................................477
17.2.1 Interpretation of the Logistic Coefficients...........................................................................................................477
17.2.1.1 Dichotomous Regressors........................................................................................................................477
17.2.1.2 Polytomous Regressors..........................................................................................................................478
17.2.1.3 Continuous Regressors and Linearity.................................................................................................479
17.2.2 Confidence Interval and Test of Hypothesis on Logistic Coefficients............................................................480
17.3 Issues in Logistic Regression..............................................................................................................................................482
17.3.1 Conditional Logistic for Matched Data...............................................................................................................482
17.3.2 Polytomous Dependent..........................................................................................................................................483
17.3.2.1 Nominal Categories of the Dependent: Multinomial Logistic.........................................................483
17.3.2.2 Ordinal Categories of the Dependent Variable...................................................................................483
xxiv Contents

17.4 Some Models for Qualitative Data and Generalizations................................................................................................484

17.4.1 Cox Regression for Hazards..................................................................................................................................484
17.4.2 Classification and Regression Tree.......................................................................................................................485
17.4.3 Further Generalizations.........................................................................................................................................486
17.4.3.1 Generalized Linear Models...................................................................................................................486
17.4.3.2 Generalized Estimating Equations.......................................................................................................486
17.4.4 Propensity Score Approach...................................................................................................................................487
17.5 Strength of Relationship in Qualitative Variables...........................................................................................................488
17.5.1 Both Variables Qualitative.....................................................................................................................................488
17.5.1.1 Dichotomous Categories........................................................................................................................488
17.5.1.2 Polytomous Categories: Nominal.........................................................................................................490
17.5.1.3 Proportional Reduction in Error (PRE)................................................................................................491
17.5.1.4 Polytomous Categories: Ordinal Association.....................................................................................492
17.5.2 One Qualitative and the Other Quantitative Variable......................................................................................494
17.5.2.1 Coefficient of Determination as a Measure of the Degree of Relationship....................................494
17.5.2.2 Biserial Correlation.................................................................................................................................495
17.5.3 Agreement in Qualitative Measurements (Matched Pairs)..............................................................................495
17.5.3.1 Meaning of Qualitative Agreement......................................................................................................495
17.5.3.2 Cohen Kappa............................................................................................................................................496
17.5.3.3 Agreement Charts...................................................................................................................................497
References........................................................................................................................................................................................498
Exercises...........................................................................................................................................................................................499

18. Survival Analysis..........................................................................................................................................................................503

18.1 Life Expectancy....................................................................................................................................................................503
18.1.1 Life Table..................................................................................................................................................................504
18.1.2 Other Forms of Life Expectancy...........................................................................................................................507
18.1.2.1 Potential Years of Life Lost....................................................................................................................507
18.1.2.2 Healthy Life Expectancy........................................................................................................................507
18.1.2.3 Application to Other Setups..................................................................................................................507
18.2 Analysis of Survival Data...................................................................................................................................................508
18.2.1 Nature of Survival Data.........................................................................................................................................508
18.2.1.1 Types of Censoring.................................................................................................................................508
18.2.1.2 Collection of Survival Time Data..........................................................................................................509
18.2.1.3 Statistical Measures of Survival............................................................................................................510
18.2.2 Survival Observed in Time Intervals: Life Table Method................................................................................510
18.2.2.1 Life Table Method...................................................................................................................................510
18.2.2.2 Survival Function....................................................................................................................................511
18.2.3 Continuous Observation of Survival Time: Kaplan–Meier Method...............................................................513
18.2.3.1 Kaplan–Meier Method............................................................................................................................513
18.2.3.2 Using the Survival Curve for Some Estimations................................................................................515
18.2.3.3 Standard Error of Survival Rate (K–M Method).................................................................................515
18.2.3.4 Hazard Function.....................................................................................................................................516
18.3 Issues in Survival Analysis.................................................................................................................................................517
18.3.1 Comparison of Survival in Two Groups..............................................................................................................517
18.3.1.1 Comparing Survival Rates.....................................................................................................................518
18.3.1.2 Comparing Survival Experience: Log-Rank Test...............................................................................519
18.3.2 Factors Affecting the Chance of Survival: Cox Model......................................................................................521
18.3.2.1 Parametric Models..................................................................................................................................521
18.3.2.2 Cox Model for Survival..........................................................................................................................522
18.3.2.3 Proportional Hazards.............................................................................................................................522
18.3.3 Sample Size for Hazard Ratios and Survival Studies.......................................................................................524
References........................................................................................................................................................................................525
Exercises...........................................................................................................................................................................................526
Contents xxv

19. Simultaneous Consideration of Several Variables.................................................................................................................529

19.1 Scope of Multivariate Methods..........................................................................................................................................529
19.1.1 Essentials of a Multivariate Setup........................................................................................................................530
19.1.2 Statistical Limitation on the Number of Variables.............................................................................................530
19.2 Dependent and Independent Sets of Variables................................................................................................................531
19.2.1 Dependents and Independents Both Quantitative............................................................................................531
19.2.1.1 Canonical Correlation.............................................................................................................................531
19.2.1.2 Multivariate Multiple Regression.........................................................................................................532
19.2.1.3 Path Analysis...........................................................................................................................................535
19.2.2 Quantitative Dependents and Qualitative Independents: Multivariate Analysis of Variance...................536
19.2.2.1 Regular MANOVA..................................................................................................................................537
19.2.2.2 MANOVA for Repeated Measures.......................................................................................................539
19.2.3 Classification of Subjects into Known Groups: Discriminant Analysis.........................................................539
19.2.3.1 Discriminant Functions.........................................................................................................................539
19.2.3.2 Classification Rule...................................................................................................................................540
19.2.3.3 Classification Accuracy..........................................................................................................................540
19.3 Identification of Structure in the Observations...............................................................................................................543
19.3.1 Identification of Clusters of Subjects: Cluster Analysis.....................................................................................543
19.3.1.1 Measures of Similarity...........................................................................................................................543
19.3.1.2 Hierarchical Agglomerative Algorithm.............................................................................................. 544
19.3.1.3 Deciding on the Number of Natural Clusters....................................................................................545
19.3.2 Identification of Unobservable Underlying Factors: Factor Analysis..............................................................546
19.3.2.1 Factor Analysis........................................................................................................................................547
19.3.2.2 Steps for Factor Analysis........................................................................................................................548
19.3.2.3 Features of a Successful Factor Analysis.............................................................................................549
19.3.2.4 Factor Scores.............................................................................................................................................550
References........................................................................................................................................................................................550
Exercises...........................................................................................................................................................................................551

20. Quality Considerations................................................................................................................................................................555

20.1 Statistical Quality Control in Medical Care.....................................................................................................................555
20.1.1 Statistical Control of Medical Care Errors..........................................................................................................556
20.1.1.1 Adverse Patient Outcomes.....................................................................................................................556
20.1.1.2 Monitoring Fatality.................................................................................................................................557
20.1.1.3 Limits of Tolerance..................................................................................................................................557
20.1.2 Quality of Lots.........................................................................................................................................................558
20.1.2.1 Lot Quality Method................................................................................................................................558
20.1.2.2 LQAS in Health Assessment..................................................................................................................558
20.1.3 Quality Control in a Medical Laboratory............................................................................................................559
20.1.3.1 Control Chart...........................................................................................................................................559
20.1.3.2 Cusum Chart............................................................................................................................................560
20.1.3.3 Other Errors in a Medical Laboratory..................................................................................................561
20.1.3.4 Six Sigma Methodology.........................................................................................................................561
20.1.3.5 Nonstatistical Issues...............................................................................................................................561
20.2 Quality of Measurement Instruments..............................................................................................................................562
20.2.1 Validity of Instruments..........................................................................................................................................562
20.2.1.1 Types of Validity......................................................................................................................................562
20.2.2 Reliability of Instruments......................................................................................................................................563
20.2.2.1 Internal Consistency...............................................................................................................................563
20.2.2.2 Cronbach Alpha.......................................................................................................................................564
20.2.2.3 Test–Retest Reliability.............................................................................................................................565
20.3 Quality of Statistical Models: Robustness........................................................................................................................566
20.3.1 Limitations of Statistical Models..........................................................................................................................566
xxvi Contents

20.3.2 Validation of the Models........................................................................................................................................567

20.3.2.1 Internal Validation..................................................................................................................................567
20.3.2.2 External Validation.................................................................................................................................568
20.3.3 Sensitivity Analysis and Uncertainty Analysis.................................................................................................568
20.3.3.1 Sensitivity Analysis................................................................................................................................568
20.3.3.2 Uncertainty Analysis..............................................................................................................................569
20.3.4 Resampling..............................................................................................................................................................570
20.3.4.1 Bootstrapping..........................................................................................................................................570
20.3.4.2 Jackknife Resampling.............................................................................................................................571
20.3.4.3 Optimistic Index......................................................................................................................................571
20.4 Quality of Data.....................................................................................................................................................................572
20.4.1 Errors in Measurement..........................................................................................................................................572
20.4.1.1 Lack of Standardization in Definitions................................................................................................572
20.4.1.2 Lack of Care in Obtaining or Recording Information.......................................................................572
20.4.1.3 Inability of the Observer to Secure Confidence of the Respondent.................................................573
20.4.1.4 Bias of the Observer................................................................................................................................573
20.4.1.5 Variable Competence of the Observers................................................................................................573
20.4.2 Missing Values........................................................................................................................................................573
20.4.2.1 Approaches for Missing Values............................................................................................................ 574
20.4.2.2 Handling Nonresponse..........................................................................................................................575
20.4.2.3 Imputations..............................................................................................................................................576
20.4.2.4 Intention-to-Treat (ITT) Analysis..........................................................................................................576
20.4.3 Lack of Standardization in Values........................................................................................................................578
20.4.3.1 Standardization Methods Already Described....................................................................................578
20.4.3.2 Standardization for Calculating Adjusted Rates................................................................................578
20.4.3.3 Standardized Mortality Ratio................................................................................................................579
References........................................................................................................................................................................................580
Exercises...........................................................................................................................................................................................581

21. Statistical Fallacies........................................................................................................................................................................583

21.1 Problems with the Sample..................................................................................................................................................583
21.1.1 Biased Sample..........................................................................................................................................................583
21.1.1.1 Survivors..................................................................................................................................................584
21.1.1.2 Volunteers.................................................................................................................................................584
21.1.1.3 Clinic Subjects..........................................................................................................................................584
21.1.1.4 Publication Bias.......................................................................................................................................585
21.1.1.5 Inadequate Specification of the Sampling Method............................................................................585
21.1.1.6 Abrupt Series...........................................................................................................................................585
21.1.2 Inadequate Size of Sample.....................................................................................................................................585
21.1.2.1 Size of Sample Not Adequate................................................................................................................585
21.1.2.2 Problems with Calculation of Sample Size..........................................................................................586
21.1.3 Incomparable Groups.............................................................................................................................................586
21.1.3.1 Differential in Group Composition......................................................................................................587
21.1.3.2 Differential Compliance.........................................................................................................................588
21.1.3.3 Variable Periods of Exposure................................................................................................................588
21.1.3.4 Improper Denominator..........................................................................................................................589
21.1.4 Mixing of Distinct Groups.....................................................................................................................................590
21.1.4.1 Effect on Regression................................................................................................................................590
21.1.4.2 Effect on Shape of the Distribution......................................................................................................591
21.1.4.3 Lack of Intragroup Homogeneity.........................................................................................................591
21.2 Inadequate Analysis............................................................................................................................................................592
21.2.1 Ignoring Reality......................................................................................................................................................592
21.2.1.1 Looking for Linearity.............................................................................................................................592
21.2.1.2 Overlooking Assumptions.....................................................................................................................592
21.2.1.3 Selection of Inappropriate Variables....................................................................................................593
Contents xxvii

21.2.1.4 Area under the (Concentration) Curve................................................................................................593

21.2.1.5 Further Problems with Statistical Analysis.........................................................................................594
21.2.1.6 Anomalous Person-Years.......................................................................................................................594
21.2.1.7 Problems with Intention-to-Treat Analysis and Equivalence...........................................................595
21.2.2 Choice of Analysis..................................................................................................................................................595
21.2.2.1 Mean or Proportion?...............................................................................................................................595
21.2.2.2 Forgetting Baseline Values.....................................................................................................................596
21.2.3 Misuse of Statistical Packages...............................................................................................................................596
21.2.3.1 Overanalysis............................................................................................................................................597
21.2.3.2 Data Dredging.........................................................................................................................................597
21.2.3.3 Quantitative Analysis of Codes............................................................................................................597
21.2.3.4 Soft Data versus Hard Data...................................................................................................................597
21.3 Errors in Presentation of Findings....................................................................................................................................597
21.3.1 Misuse of Percentages and Means.......................................................................................................................598
21.3.1.1 Misuse of Percentages.............................................................................................................................598
21.3.1.2 Misuse of Means......................................................................................................................................599
21.3.1.3 Unnecessary Decimals...........................................................................................................................599
21.3.2 Problems in Reporting.......................................................................................................................................... 600
21.3.2.1 Incomplete Reporting............................................................................................................................ 600
21.3.2.2 Overreporting..........................................................................................................................................601
21.3.2.3 Selective Reporting.................................................................................................................................601
21.3.2.4 Self-Reporting versus Objective Measurement..................................................................................601
21.3.2.5 Misuse of Graphs....................................................................................................................................601
21.4 Misinterpretation.................................................................................................................................................................602
21.4.1 Misuse of P-Values..................................................................................................................................................602
21.4.1.1 Magic Threshold of 0.05.........................................................................................................................602
21.4.1.2 One-Tailed or Two-Tailed P-Values.......................................................................................................603
21.4.1.3 Multiple Comparisons............................................................................................................................603
21.4.1.4 Dramatic P-Values...................................................................................................................................603
21.4.1.5 P-Values for Nonrandom Sample..........................................................................................................603
21.4.1.6 Assessment of “Normal” Condition Involving Several Parameters................................................604
21.4.1.7 Absence of Evidence Is Not Evidence of Absence..............................................................................604
21.4.2 Correlation versus Cause–Effect Relationship...................................................................................................604
21.4.2.1 Criteria for Cause–Effect........................................................................................................................605
21.4.2.2 Other Considerations..............................................................................................................................606
21.4.3 Sundry Issues..........................................................................................................................................................606
21.4.3.1 Diagnostic Test is Only an Additional Adjunct..................................................................................606
21.4.3.2 Medical Significance versus Statistical Significance..........................................................................606
21.4.3.3 Interpretation of Standard Error of p......................................................................................................606
21.4.3.4 Univariate Analysis but Multivariate Conclusions............................................................................607
21.4.3.5 Limitation of Relative Risk....................................................................................................................607
21.4.3.6 Misinterpretation of Improvements.....................................................................................................607
21.4.4 Final Comments......................................................................................................................................................608
References........................................................................................................................................................................................609
Exercises........................................................................................................................................................................................... 610

Brief Solutions and Answers to the Selected Exercise.................................................................................................................. 611

Appendix A: Statistical Software......................................................................................................................................................631
Appendix B: Some Statistical Tables................................................................................................................................................637
Appendix C: Solution Illustrations Using R.................................................................................................................................. 643
Index........................................................................................................................................................................................................689
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 TABLE

PROLOGUE 7
I. — DEUX HOMMES, DEUX CHIMÈRES 23
II. — LES CAVALIERS… 34
III. — … ET LEUR MONTURE 55
IV. — PROPOS ENTRE CIEL ET TERRE 64
V. — LE JOUR VIOLET 77
VI. — SUR LA PIERRE BRUNE 91
VII. — CEINTRAS ÉGARE SON OMBRE ET SA RAISON 101
VIII. — LA FACE AURÉOLÉE D’ÉTOILES 118
IX. — HEURES D’ATTENTE 130
X. — L’ÊTRE SE MONTRE 143
XI. — EXCURSIONS SOUTERRAINES 163
XII. — FAUX DÉPART 189
XIII. — L’AGONIE DE LA LUMIÈRE 206
XIV. — ÉCRIT SOUS LA DICTÉE DE LA MORT 226
ÉPILOGUE 233
 ACHEVÉ D’IMPRIMER
Le vingt-sept mai mil neuf cent sept
PAR

ARRAULT ET Cie
A TOURS
pour le
MERCVRE
DE
FRANCE
*** END OF THE PROJECT GUTENBERG EBOOK LE PEUPLE DU
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