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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 Basic Statistics and Pharmaceutical
Trials, Second Edition Statistical Applications, Second Edition
Shein-Chung Chow and Mark Chang James E. De Muth
Adaptive Designs for Sequential Bayesian Adaptive Methods for
Treatment Allocation Clinical Trials
Alessandro Baldi Antognini Scott M. Berry, Bradley P. Carlin,
and Alessandra Giovagnoli J. Jack Lee, and Peter Muller
Adaptive Design Theory and Bayesian Analysis Made Simple:
Implementation Using SAS and R, An Excel GUI for WinBUGS
Second Edition Phil Woodward
Mark Chang Bayesian Designs for Phase I–II
Advanced Bayesian Methods for Clinical Trials
Medical Test Accuracy Ying Yuan, Hoang Q. Nguyen,
Lyle D. Broemeling and Peter F. Thall
Analyzing Longitudinal Clinical Trial Data: Bayesian Methods for Measures
A Practical Guide of Agreement
Craig Mallinckrodt and Ilya Lipkovich Lyle D. Broemeling
Applied Biclustering Methods for Big Bayesian Methods for Repeated Measures
and High-Dimensional Data Using R Lyle D. Broemeling
Adetayo Kasim, Ziv Shkedy, Bayesian Methods in Epidemiology
Sebastian Kaiser, Sepp Hochreiter, Lyle D. Broemeling
and Willem Talloen
Bayesian Methods in Health Economics
Applied Meta-Analysis with R Gianluca Baio
Ding-Geng (Din) Chen and Karl E. Peace
Bayesian Missing Data Problems: EM,
Applied Surrogate Endpoint Evaluation Data Augmentation and Noniterative
Methods with SAS and R Computation
Ariel Alonso, Theophile Bigirumurame, Ming T. Tan, Guo-Liang Tian,
Tomasz Burzykowski, Marc Buyse, and Kai Wang Ng
Geert Molenberghs, Leacky Muchene,
Nolen Joy Perualila, Ziv Shkedy,
and Wim Van der Elst
Published Titles

Bayesian Modeling in Bioinformatics Clinical Trial Optimization Using R

Dipak K. Dey, Samiran Ghosh, Alex Dmitrienko and Erik Pulkstenis
and Bani K. Mallick Cluster Randomised Trials:
Benefit-Risk Assessment in Second Edition
Pharmaceutical Research and Richard J. Hayes and Lawrence H. Moulton
Development Computational Methods in Biomedical
Andreas Sashegyi, James Felli, Research
and Rebecca Noel Ravindra Khattree and Dayanand N. Naik
Benefit-Risk Assessment Methods in Computational Pharmacokinetics
Medical Product Development: Bridging Anders Källén
Qualitative and Quantitative Assessments
Confidence Intervals for Proportions
Qi Jiang and Weili He
and Related Measures of Effect Size
Bioequivalence and Statistics in Clinical Robert G. Newcombe
Pharmacology, Second Edition
Controversial Statistical Issues in
Scott Patterson and Byron Jones
Clinical Trials
Biosimilar Clinical Development: Shein-Chung Chow
Scientific Considerations and New
Data Analysis with Competing Risks
Methodologies
and Intermediate States
Kerry B. Barker, Sandeep M. Menon,
Ronald B. Geskus
Ralph B. D’Agostino, Sr., Siyan Xu, and Bo Jin
Data and Safety Monitoring Committees
Biosimilars: Design and Analysis of
in Clinical Trials, Second Edition
Follow-on Biologics
Jay Herson
Shein-Chung Chow
Design and Analysis of Animal Studies
Biostatistics: A Computing Approach
in Pharmaceutical Development
Stewart J. Anderson
Shein-Chung Chow and Jen-pei Liu
Cancer Clinical Trials: Current and
Design and Analysis of Bioavailability
Controversial Issues in Design and
and Bioequivalence Studies, Third Edition
Analysis
Shein-Chung Chow and Jen-pei Liu
Stephen L. George, Xiaofei Wang,
and Herbert Pang Design and Analysis of Bridging Studies
Jen-pei Liu, Shein-Chung Chow,
Causal Analysis in Biomedicine and
and Chin-Fu Hsiao
Epidemiology: Based on Minimal
Sufficient Causation Design & Analysis of Clinical Trials for
Mikel Aickin Economic Evaluation & Reimbursement:
An Applied Approach Using SAS & STATA
Clinical and Statistical Considerations in
Iftekhar Khan
Personalized Medicine
Claudio Carini, Sandeep Menon, and Mark Chang Design and Analysis of Clinical Trials
for Predictive Medicine
Clinical Trial Data Analysis Using R
Shigeyuki Matsui, Marc Buyse,
Ding-Geng (Din) Chen and Karl E. Peace
and Richard Simon
Clinical Trial Data Analysis Using R and SAS,
Design and Analysis of Clinical Trials with
Second Edition
Time-to-Event Endpoints
Ding-Geng (Din) Chen, Karl E. Peace,
Karl E. Peace
and Pinggao Zhang
Design and Analysis of Non-Inferiority Trials
Clinical Trial Methodology
Mark D. Rothmann, Brian L. Wiens,
Karl E. Peace and Ding-Geng (Din) Chen
and Ivan S. F. Chan
Published Titles
Difference Equations with Public Health Inference Principles for Biostatisticians
Applications Ian C. Marschner
Lemuel A. Moyé and Asha Seth Kapadia Interval-Censored Time-to-Event Data:
DNA Methylation Microarrays: Methods and Applications
Experimental Design and Statistical Ding-Geng (Din) Chen, Jianguo Sun,
Analysis and Karl E. Peace
Sun-Chong Wang and Arturas Petronis Introductory Adaptive Trial Designs:
DNA Microarrays and Related Genomics A Practical Guide with R
Techniques: Design, Analysis, and Mark Chang
Interpretation of Experiments Joint Models for Longitudinal and Time-
David B. Allison, Grier P. Page, to-Event Data: With Applications in R
T. Mark Beasley, and Jode W. Edwards Dimitris Rizopoulos
Dose Finding by the Continual Measures of Interobserver Agreement
Reassessment Method and Reliability, Second Edition
Ying Kuen Cheung Mohamed M. Shoukri
Dynamical Biostatistical Models Medical Biostatistics, Fourth Edition
Daniel Commenges and A. Indrayan
Hélène Jacqmin-Gadda
Meta-Analysis in Medicine and
Elementary Bayesian Biostatistics Health Policy
Lemuel A. Moyé Dalene Stangl and Donald A. Berry
Emerging Non-Clinical Biostatistics in Methods in Comparative Effectiveness
Biopharmaceutical Development and Research
Manufacturing Constantine Gatsonis and Sally C. Morton
Harry Yang
Mixed Effects Models for the Population
Empirical Likelihood Method in Approach: Models, Tasks, Methods
Survival Analysis and Tools
Mai Zhou Marc Lavielle
Essentials of a Successful Biostatistical Modeling to Inform Infectious Disease
Collaboration Control
Arul Earnest Niels G. Becker
Exposure–Response Modeling: Methods Modern Adaptive Randomized Clinical
and Practical Implementation Trials: Statistical and Practical Aspects
Jixian Wang Oleksandr Sverdlov
Frailty Models in Survival Analysis Monte Carlo Simulation for the
Andreas Wienke Pharmaceutical Industry: Concepts,
Fundamental Concepts for New Clinical Algorithms, and Case Studies
Trialists Mark Chang
Scott Evans and Naitee Ting
Multiregional Clinical Trials for
Generalized Linear Models: A Bayesian Simultaneous Global New Drug
Perspective Development
Dipak K. Dey, Sujit K. Ghosh, and Joshua Chen and Hui Quan
Bani K. Mallick
Multiple Testing Problems in
Handbook of Regression and Modeling: Pharmaceutical Statistics
Applications for the Clinical and Alex Dmitrienko, Ajit C. Tamhane,
Pharmaceutical Industries and Frank Bretz
Daryl S. Paulson
Published Titles

Noninferiority Testing in Clinical Trials: Statistical Design and Analysis of Clinical

Issues and Challenges Trials: Principles and Methods
Tie-Hua Ng Weichung Joe Shih and Joseph Aisner
Optimal Design for Nonlinear Response Statistical Design and Analysis of
Models Stability Studies
Valerii V. Fedorov and Sergei L. Leonov Shein-Chung Chow
Patient-Reported Outcomes: Statistical Evaluation of Diagnostic
Measurement, Implementation and Performance: Topics in ROC Analysis
Interpretation Kelly H. Zou, Aiyi Liu, Andriy Bandos,
Joseph C. Cappelleri, Kelly H. Zou, Lucila Ohno-Machado, and Howard Rockette
Andrew G. Bushmakin, Jose Ma. J. Alvir, Statistical Methods for Clinical Trials
Demissie Alemayehu, and Tara Symonds Mark X. Norleans
Quantitative Evaluation of Safety in Drug Statistical Methods for Drug Safety
Development: Design, Analysis and Robert D. Gibbons and Anup K. Amatya
Reporting
Statistical Methods for Healthcare
Qi Jiang and H. Amy Xia
Performance Monitoring
Quantitative Methods for Alex Bottle and Paul Aylin
HIV/AIDS Research
Statistical Methods for Immunogenicity
Cliburn Chan, Michael G. Hudgens, and
Assessment
Shein-Chung Chow
Harry Yang, Jianchun Zhang, Binbing Yu,
Quantitative Methods for Traditional and Wei Zhao
Chinese Medicine Development
Statistical Methods in Drug Combination
Shein-Chung Chow
Studies
Randomized Clinical Trials of Wei Zhao and Harry Yang
Nonpharmacological Treatments
Statistical Testing Strategies in the
Isabelle Boutron, Philippe Ravaud,
Health Sciences
and David Moher
Albert Vexler, Alan D. Hutson,
Randomized Phase II Cancer and Xiwei Chen
Clinical Trials
Statistics in Drug Research:
Sin-Ho Jung
Methodologies and Recent
Repeated Measures Design with Developments
Generalized Linear Mixed Models for Shein-Chung Chow and Jun Shao
Randomized Controlled Trials
Statistics in the Pharmaceutical Industry,
Toshiro Tango
Third Edition
Sample Size Calculations for Clustered Ralph Buncher and Jia-Yeong Tsay
and Longitudinal Outcomes in Clinical
Survival Analysis in Medicine and
Research
Genetics
Chul Ahn, Moonseong Heo,
Jialiang Li and Shuangge Ma
and Song Zhang
Theory of Drug Development
Sample Size Calculations in Clinical
Eric B. Holmgren
Research, Third Edition
Shein-Chung Chow, Jun Shao, Hansheng Translational Medicine: Strategies and
Wang, and Yuliya Lokhnygina Statistical Methods
Dennis Cosmatos and Shein-Chung Chow
Statistical Analysis of Human Growth
and Development
Yin Bun Cheung
http://taylorandfrancis.com
Medical Biostatistics
Fourth Edition

Abhaya Indrayan
Rajeev Kumar Malhotra
CRC Press
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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
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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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It has been further suggested, that the description of my excentric
Bar Press was not sufficiently explicit. I have therefore added the
figure 2 of Plate 22, to assist in elucidating that description. I had,
perhaps made an undue use of the principle of virtual velocities by
saying, too concisely, (page 174) that “as the whole approaches
toward B C, the relative motion (of the cheeks s and B) becomes
insensible, the circles parallel, and consequently, the power infinite.”
It is however vulgarly said that power cannot be gained without
losing time—which implies that if time is lost, power will be gained:
and the principle of virtual velocities says the same thing, though in
more appropriate terms—that if a small movement be given to a
system of bodies actually counterpoising each other, the quantity of
motion with which one body ascends, and the other descends
perpendicularly, will be equal: so that, as remarked in page 50, by
“whatever means a slow motion is obtained, dependent on that of a
moving force, the power is great in the same proportion.” Now, in
the eccentric Bar Press, (see fig. 2) this is so in an eminent degree:
for when the bars are in the position A B, the distance of the cheeks
is equal to B s; and they must move, circularly, as far as A f, to bring
them closer to each other by the quantity s a: dividing therefore, the
distance B g by the line s a, we find (near enough for practice) the
power of the Machine within the limits A g B. It is nearly as 10 to 1.
In like manner this power at A e g, is equal to the arc e g divided by
the line f b; and at A l n to the arc l n divided by the line d k, namely
by the difference of the lines k l and m n. From the above it appears
that the nearing motion of the cheeks of the press, becomes slower
and slower as the bars A and C come nearer to the point C:
insomuch that the difference between the lines m n and o p is nearly
imperceptible, and that between the lines o p and C q entirely so.
But according to the above process, the distance p C should be
divided by this imperceptible line, to find the power of the press at
the point C; which therefore is immense. Another proof of this may
be drawn from the supposition (see fig. 3) that the small lever a d is
turned round the centre o by a bar o C fixed to it, and of equal
length with the line A C fig. 2. Fig. 3 shews that the lines or bars C
d, and a C are moved endwise by the circular action of the points a
and d; and therefore (by statics) their motion is the same as though
caused by the perpendiculars b o and o c let down from the centre
o, on each of them. Hence the power of this Machine is found by
dividing the distance o C by the sum of the lines b o and o c; which
sum (when these lines vanish by the union of the bars over the
centre) becomes infinitely small: the quotient of which division
therefore is infinitely great—as was to be shewn.
 OF

A PUNCH MACHINE,
For Engravers to Calico Printers.

The usual method of making Punches for engraving Copper

Cylinders, (otherwise than by the milling system) is to cut the
desired pattern on a die, and then to transfer that pattern by blows
or pressure to the punch, from which it is again transferred to the
cylinder. My Machine in this operation, unites motion to the needful
pressure; and thus renders the result more easy and complete. This
effect I could the better ensure, because the surfaces of my punches
are essentially convex, or rather cylindrical; as will appear when my
engraving Machine comes to be described. Their convexity however,
can be diminished at pleasure—whence this Machine is capable of
offering useful assistance to a maker of flat punches.
In Plate 23, A B fig. 1 and 2, is the body of the Machine, with the
vibrating bar C D laid upon it; reposing especially on the correct and
level parts of the body at a b; this bar contains the die c, with which
it vibrates between the cheeks B R, as impelled by the screws E F,
it’s centre of motion being the pin P, duly supported by the strong
shoulder A. In a line with the bar C D, is placed a second vibrator G,
containing the steel d, that is to become a punch, already rounded
into the cylindrical shape it must have when finished. This vibrator
has it’s centre of motion at e fig. 1, and it need not be added that
the curvature of the punch depends on it’s distance e d from that
centre: for the centre of the long bar C D is so distant as to have
little influence on it’s formation. Further, the cap or bridge H I, which
furnishes a centre for the smaller vibrator G, can be brought forward
to any useful position by the nuts K L: that cap sliding horizontally
between the cheeks M N as directed by the small arms m n. This
motion, then, taken from the nuts K L, serves to impress the work of
the die on the steel prepared for the punch; and this being done to a
first degree, both the handles O Q, are laid hold of: and by turning
the screws the same way one of them goes forward and the other
recedes, until the punch and die have been in contact over half their
surface. At this moment both screws are turned backward, and the
motions of the two vibrators reversed: by the repetition of which
alternate motions accompanied by the needful pressure, the whole
pattern is transferred from the die to the punch—when the latter is
taken out of the Machine, and filed up in the usual method.
It should be observed, that the smaller vibrator G can be displaced
with ease when the nuts K L are withdrawn: and this should be
frequently done to examine the progress of the impression. Nor is
there any difficulty in re-entering the figures. In a word, the
perfection of this process depends more on much motion than on
violent pressure: whence this facility of re-entering is a desirable
property. This Machine is usually laid on a bench or tressel, with a
long mortice in it, into which the feather x of this Machine enters so
as to be firmly fixed.
 OF

A DIFFERENTIAL PUNCH
MACHINE
For Engravers.

I was the rather induced to attend a second time to the differential

Steel-yard, because I had it in contemplation to apply that principle
to the present purpose; since, to make flat punches, is to some
engravers a more desirable thing than to make cylindrical ones. I am
not fully persuaded that it is even possible to transfer a large
pattern, from a flat die to a flat punch, by any pressure acting
simultaneously on the whole surface. In those cases, if there is
much work, the whole surface goes down; and the parts that form
the pattern do not rise. But, all that can be done in this case, is, I
believe, feasible by the Machine now to be described.
Plate 23, gives in fig. 3 and 4, a representation of this Machine; A B
and C D, are two slides, having wedge-formed ends above A and
below D, well made, well steeled, and well tempered. One of these
slides contains the die and the other the steel prepared for the
punch (see B C). These wedge-ended slides are embraced by two
levers E F, G H, which are themselves connected by two stirrups I K
and L M, better shewn at fig. 3. These latter are supposed in fig. 4
to be broken at L M, to leave the levers E F and G H more visible.
They are formed, at the turning below, into wedge-like edges a b;
well hardened, that clip the nicks c d of the lower lever: and at the
top of the Machine their arms e f, pass through the caps m n, above
which they are nutted like a common bolt, and made to press
strongly on the main lever E F. The stirrup placed to the right hand,
presses in particular, by it’s cap n, on the moveable step o, exactly in
the notch q: this step having a backward and forward motion
communicated by the regulating screw p. Before beginning to use
this Machine, I make all it’s arms A E, A g, D e, D d, equal, when it’s
power (see page 162) is infinite; and to put it in a working state, I
turn the screw p backward, say one half round: which motion (if the
screw has 20 threads to the inch) makes a difference in the two
arms A r and A q of 1⁄40 of an inch, and the virtual centre of the
Machine is therefore 1⁄80 of an inch from the former point A, that is
from the edge of the slide A in this fig. 3. Supposing now, the whole
working lever E F to be 3 feet, and the workman’s force to be
100lbs. in each arm, then by displacing the lever to any proper
distance from F towards f, he will produce a pressure between the
die and the punch of 200lbs. multiplied by 1440, the number of
times that 1⁄80 of an inch is contained in 18 inches.—That is, a
pressure of two hundred and eighty-eight thousand pounds!
I have been seduced, by the anticipated brilliancy of this result, from
the regular course of description,—and the plate w x, y z, which
forms the base or frame of this whole Machine has not yet been
spoken of. But that plate is supposed screwed down to a horizontal
bench, at or near the height of a man’s breast; the slides or cases
are fastened to it, and the man is supposed to work the Machine
nearly as he would a die-stock in tapping a screw. This however is
not indispensable; the Machine might be placed vertically, and these
motions given by any proper mover; or a weight may be suspended
to the arm F, so as to add continuity to pressure. It is however
important, that the position should comport with the frequent
extraction of the punch in order to examine the progress of the
work, or cut away any redundant metal. I have before given it as my
opinion that much could not be expected from mere pressure: but
this is a pressure of a peculiar kind, consisting of immense powers
with very short motions. In this respect it is just what was wanted,
as it can be renewed and repeated frequently, without loss of time.
And the more to facilitate this delicate operation, the hollow slides or
cases B C, are made slightly pyramidical, to be furnished with set-
screws on the four sides, by which to change the place of bearing;
and thus to meet the case of a flat punch with the advantage of
impressing it by portions, so as to have only to finish it by brute
pressure.
The foregoing application of the principle of the differential Steel-
yard, is, I think, important, and founded on unobjectionable
principles; for although by changing alone the place of the step o,
we disturb a little the parallelism of the stirrups I K, and L M; we do
it not enough to produce, any material change in the theoretical
result. With respect then to the lesser properties of this Machine, I
leave them with confidence in the hands of those whom they most
concern—who doubtless, will treat them with greater practical utility
than I could myself hope to do.
 OF

A MACHINE
For Moulding Nails.

This Machine offers, I think, a valuable application of a well known

Instrument: or rather of the principle on which it is founded. I allude
to that parallel ruler which, by means of an additional joint, keeps
it’s members not only parallel, but directly opposite each other. In
my Machine for moulding Nails, I wanted to give motions to the two
plates different, yet dependent on each other. Supposing then, (Plate
24 fig. 1, 2, 3, 4,) the upper plate a b, to be moved up and down by
a lever, a screw-press, or any other first mover, I connect the under
plate c d, with it by two (or four) strong parallel rulers e f, in such a
manner, that when the plate a b is drawn upward it shall extend the
arms of the ruler almost to a straight line, as represented in fig. 4;
and then carry the under plate with it: and when it comes down
again (see fig. 3) it shall not carry down the said under plate, until
the same arms are bent into the position f g; that is, till the two
plates touch each other: the use of which arrangement I will now
explain.
The under side of the upper plate a b, is ground perfectly flat, and
bored at proper distances with holes to receive and hold the
punches which represent the shanks of the nails that are to be
moulded. The lower plate c d is ground true both on it’s upper and
under surfaces; the first to fit the under surface of the upper plate,
and the under surface to impress a perfect plane on the sand below
it. This under surface, shewn in an inverted position at fig. 2, is
moreover covered with proper prints 1, 2, 3, &c. to form the heads
of the nails in question, and with proper gets (jets?) 3, 5, 6, &c. for
conducting the metal to every part of the surface. I mean models in
relief of those gets; and the under plate is further pierced with
holes, placed exactly like those in the upper plate, bored indeed
from that (and through the aforesaid prints of the nail-heads) after
the parallel joints e f have been affixed. Now on another level plate
with proper ledges, the sand boxes or flasks, fig. 5 and 6, have been
prepared; and have received an obtuse pyramidical form at one
stroke from a competent press, the construction of which is easily
conceived: or this might be done by hand, if preferred. These boxes,
in-fine, are successively brought under the before described
mechanism while in the state represented in fig. 3, in which all the
nail models are protruded through the under plate as at 1, 2, 3. The
moulder now gives a stroke under the following circumstances:—
Both the plates drop together and the nail models pierce the sand
while the under plate makes it’s surface perfectly level: but when
that motion is reversed, it is not the under plate which first rises, but
the upper—by which the nail models are drawn out of their holes
without disturbing the sand, for this is kept to it’s place by the under
plate: and when, by the continued motion upward of the upper
plate, the parallel joints are duly extended, and the nail models quite
extracted; then, and not till then, the under plate leaves the
compressed sand, in which are moulded as many scores of nails as
the mould has been made for—and that, in a space of time almost
imperceptible.
I shall conclude the subject by observing, that the counter flask or
box for closing this mould is made in the same way, by a smooth
plate prepared in the same manner; and which must fit the former,
because they are both perfectly level surfaces.
 OF

A FIRE ENGINE
Giving Power, while heating Rooms, Liquids,
&c.

This Machine, though conceived many years ago, can hardly yet be
called an invention—if material existence is necessary to justify that
appellation: for I have never seen it in action. It may possibly be one
of those fascinating conceptions of which my noble friend the late
Earl Stanhope used to say—“’tis a beautiful invention—but ’twill not
do;” yet I give it with some confidence, because of the great utility it
would present, if it’s chief properties should fulfil my expectations.
The principal idea on which it is founded, is this: to use, as power,
the expansion of that air which feeds the fire; and again to employ
it’s heat heating liquids or rooms, or any similar purpose. The form I
have given to the Machine is by no means the only one it admits;
nor perhaps the best: but it was indispensable to give the idea
(which I hope is not an “airy nothing”) “a local habitation and a
name.”
It consists, then, of two cylinders, lying horizontally, of nearly equal
length, but of unequal capacity:—one of which A B, (Plate 24, fig. 7)
is an air pump with a valve in it’s end a, and another in it’s piston,
both opening to the left. The second cylinder C D, is the working
cylinder, as much larger than the former, as may belong to the
principle of motion already announced. This cylinder receives the
piston E, which fits it nicely, but is not stuffed in the present case. (It
may perhaps be made tight by some of the methods, used to close
metallic pistons.) At all events, this piston is connected with that c,
by a frame F G H I, which embraces the whole Machine, in a
horizontal position, though here shewn in a vertical. These two
cylinders are cast in one piece, together with an upright cylinder, not
bored K; the use of which is to receive the earthen chafing dish L M,
with it’s fire, made (according to my present views) with coak or
charcoal, and lighted before it is introduced. It is needless to say,
that this vessel is let down into the cylinder K, by a kind of bucket
handle entering any pair of holes in the dish. The top of this latter
cylinder is ground to fit the flanch A N: It swings open on one of the
bolts and falls to again in a moment, to prevent loss of time in firing.
The means of doing this I do not much insist on, from their extreme
facility. Nor do I make it a condition to use this method at all. The
coak, (or perhaps the coal, or the wood) might be introduced
through an upright tube furnished with two slides, one placed close
above the top A N, and the other at a proper distance above; so as
for one to be always shut. This is nothing more than the System
used for feeding high pressure Steam Engines—only this application
is to dry substances, which forms no insuperable obstacle.
When now the Machine is fired, the pistons E, and c, are pushed
towards b and B respectively; the valve d having been previously
opened, and the valve c opening by this very motion—which thus
clears the large cylinder of it’s included air, while the air in the pump
A B, is brought into contact with the fire; whence a considerable
expansion ensues, and a pressure is created tending at the same
time to drive the piston c to the right hand, and that E to the left:
but acting in the latter case on a larger area, the whole system
moves that way, and all the air in the pump A B is driven through
the fire: where, being much heated, it acquires great elasticity and
developes considerable power—which, by any of the known
methods, may be applied to any of the known purposes.
I hope my readers will conclude here, that I allow for the
disappearance of the oxigen in this conflagration: but I expect the
expansion of the residue (together with what new vapour may be
developed) will more than compensate for that loss of volume. By
this motion then, the pump A B is again filled with cold air through
the valve a; and the piston E flying out of the cylinder C D, the hot
air it contained rushes into the pipe o, and thence goes to perform
any heating operation that may be desired. But further, this same
recession of the piston E strikes the stem of the valve d against the
cover e, and opens that valve; by which means the large piston is at
liberty to reach again it’s inner position b: where the bar b closes it’s
valve d and prepares the Machine for a new stroke. For, as before,
the pump or cylinder A B, is full of cold air, and by the backward
motion of it’s piston exposes that air to the fire in K: whence arises
the renewal of all the former phenomena.
Many ideas, and doubtless some objections, will present themselves
to the readers of these pages; of which I shall probably anticipate
some, by noticing a few less important particulars.
And first, is it not to be feared that the vertical cylinder K, and the
whole system K C D E will become too hot—nay acquire a red heat,
and thus introduce danger? The answer, I think, is that the fire must
be lessened, or the Machine enlarged, until this danger disappears:
for by heating air to any thing like a red heat (without attaining it)
the expansion will be immense: and probably beyond our wants or
wishes. The chaffing dish then (if that is used) must be lessened,
that the air from A B may partly circulate round it, instead of going
wholly through the fire: thus cooling the vertical cylinder K, and
diminishing the intensity of the heat in the working cylinder. Further,
the two cylinders C D and K, might be inserted in the bottom of a
boiler, and surrounded with water; through which also, may be
conducted the pipe O, so as to concur in the same effect of heating
that water, while the steam thus accruing from the double use of this
heat, may be made to drive an engine, heat a room, or fulfil any
common purpose.
In a word, all our difficulties on this branch of the subject, seem to
lie in excess of action: and we need only mitigate the general effect,
to render this Machine useful, safe, and commodious.
There is another objection that must be met, on pain of direct
censure, which is this: what will become of the ashes? (for smoke is
as yet out of the question) my answer is—a recess, or several, must
be found for them beyond o; to do which will not be more difficult
than to lodge any other residue. But if this Machine fulfils my views
in respect of power, this residue will be no burden. For example, if
ever a farmer should hereafter drive his plough by such an engine as
this, he will manure his land furrow by furrow with the ashes—an
idea which I must not yet indulge, lest I should be thought fanciful
beyond the due proportion.
But my mechanical impetus is not to be thus instantly checked. If
what I hope, can be realized, there are properties in this invention,
for locomotive engines, superior to any the steam engine itself can
boast. A light Machine: a light combustible: no water to carry; no
steam to condense, &c. &c. As however I have never tried this
felicitous creation, I assert nothing.
But again, this seems to be a really good method of distributing heat
in any useful direction: for there is an impulsive force which not only
requires no draught to make the fire burn, but will drive heat to any
distance through pipes of any form, and placed in any position.
There is therefore, a certain utility attached to this Machine,
whatever may be it’s merits as a power engine. Our present
methods—of destroying coals—are excellent! but our methods of
making them useful are defective in the extreme. If you have no
draught in your chimneys you are stifled with smoke. If you have
much draught, you have little heat—for the chimney swallows it, and
half your room is in Norway. Use then an impulsive system, (of some
kind) and you may send your caloric down into the cellar to be
drawn from thence as wanted, for the upper apartments.
But my subject pullulates as I proceed. This idea is by no means
exhausted. It is not an indispensable feature of it, to heat rooms
with the same air that fed the fire. For instance, if a fire were made
under the vertical cylinder K, and led into and through it by a proper
pipe, almost filling it—then the cold air of the pump A B would pass
round that pipe to the working cylinder C D, and there impel it’s
piston E as before. Not perhaps so strongly; but with an air
uncontaminated by burning, or by ashes—and therefore more
congenial with some uses of the Machine. In fact, air thus
introduced might be perfectly fit for breathing, and still get elasticity
enough from this passage, to force heat to the bottom of any room
we wished to have warmed; whereas, by using only the levity of
heated air to give it motion, we scorch the tops of rooms and
factories, and unmercifully freeze the bottoms. I must beg leave to
be a little severe on this point:—since for a thinking people, as
strangers call us, we have been extremely thoughtless in this
respect: so that as much seems now to do by way of introducing
comfort into our saloons, as was done about the year 1200, when
those chimneys were introduced that are now become a kind of
nuisance. In a word, and I am serious when I say it, the present
arrangement of our chimneys, is in my humble opinion, essentially
unphilosophical; and as such ought to be speedily discontinued or
greatly modified.
In the above pages I have laid myself open to much animadversion,
by a kind of cast for much honest fame. I have let the public into my
secret—I have thought aloud: And if the greater part of these
cogitations should prove to be imaginary, I shall only plead, that
they are drawn from the same source as the many useful Machines I
am known to have devoted to public utility.
 OF

A ROTATO-GYRATORY CHURN.

This title I confess, seems very ambitious, as applied to an utensil

for the dairy: but I had to express the combination of it’s own axis,
and those of the leaves or wings about their respective axes, while
gyrating round the common centre.

The principal shaft A B, fig. 8 and 9 of Plate 24, is the general centre
of rotation; and a b are two lighter shafts carried round that centre,
and turning at the same time on their own centres by means of the
wheels e f geering in the fixed wheel c d, (of which one half only is
drawn) and which forms part of the top of the churn. Each of the
shafts a b, carries four leaves or wings (better seen in fig. 9)
reaching from the top, nearly to the bottom of the vessel; and they
run in proper steps in the cross piece m, and also in proper collars in
the upper cross piece g h. In fine their wheels e f, and the fixed
wheel c d, which turns them, are furnished with teeth on my patent
principle; and therefore work without noise or commotion. Now, the
principal shaft A B, rests on the step B at the bottom of the vessel;
and runs, at top, in a collar formed in the metallic bridge i k, which,
fixed to the outside rim of the cover, passes directly over the centre
of the Machine. When therefore, the cream is put into the churn, (to
do which the above mechanism is taken out) the mechanism is re-
placed as now represented; and the main shaft set in motion by any
convenient power: when the side shafts a b, turned by the fixed
wheel c d, give a backward motion to the wings a b, and create a
great agitation of the cream—for, it should be remarked, that this is
not a circular motion: but each fly produces a kind of vortex round
it’s own centre, while progressing round the common centre. The
consequence of which, as above intimated, is, an unceasing
agitation of the liquid, and, I believe, the best of churning. This
however, I state as a mechanician, not having been initiated into the
secrets of the dairy properly so called.
It may finally be observed, that the leaves or partitions l n, fixed to
the sides of the churn, (beyond the reach of the moveable wings a
b) are destined to prevent still further any general motion of the
butyraceous matter; and thus to accelerate the churning process:
and further these leaves, both fixed and moveable may be pierced
with holes, like the analogous parts of other utensils of this nature.
 OF

A HELICO-CENTRIFUGAL
MACHINE,
For raising Water in great quantities.

The screw of Archimedes, is well known. When used to raise water

it is placed obliquely, in such a position as that it’s hollow threads
become more oblique to the horizon than the axis of the screw itself:
observing which practice, some have said of this Machine, that it
raises water by letting it run down: But this cannot be true. The
threads of the screw merely wedge themselves under the water, and
make it rise in a direction parallel to the axis of the screw; at the
highest end of which it falls into the upper reservoir.
I once placed a screw of this kind upright, and said (in thought) is it
then impossible to raise water by means of this screw thus placed?
The answer in a few minutes was—“not at all; there is a force would
make it easy: namely, the centrifugal force:” and this mental
soliloquy was the origin of this Invention, which, some thirty years
ago, I shewed to a public man, whom the lovers of the mechanical
arts will long remember.
In Plate 25 fig. 1, A B are two screws, perfectly like those used in
exhausting watery foundations; and named of Archimedes. They are
placed perpendicularly in the frame C D, so as to turn in the cross
bars a b, c d, fixed horizontally on the main shaft E F of the
Machine. At the bottom of this shaft, E F, (which turns in a step on
the sill G D) is a low cylindrical vessel, shewn by a section only at e
f, which dips into the under water nearly to the brim. It is used to
carry, in proper steps, the centres of the screws A B, and, being
pierced with many holes, to feed them amply, without exposing their
motion to any resistance from the stagnant water. These cylinders A
B are merely indicated as screws by the threads, dotted between h
and d and e and g, and their upper mouths are seen near a b, just
under the cross piece marked with these letters. These screws then,
are turned by the wheels i k, as actuated by the fixed wheel m n, in
the same manner as those of the churn before described; which in
fact, is a corollary from this Machine, but of much later date. To
return to the Helico-centrifugal Machine—the screws A B are
terminated above by circular plates o p (marked with the same
letters in fig. 2 and 3) intended to receive the water from the
mouths of the screw-threads a b, and carry it on to the plate q q,
which insures it’s further progress into the ring canal r s, also shewn
by a section only, to prevent confusion in the figure. Now what
raises the water in these upright screws, is, it’s own centrifugal
force, combined with the revolution of the screws: for while this
central force is urging the water outward, the screws are bringing
their sloping threads like wedges, against that tendency; and the
consequence is, that the water actually rises perpendicularly till it
flows over the ledges or rings o p, on the plate q q, and thence into
the ring canal r s, from which it is conveyed to any place desired.

If this Machine is well made and proportioned, I think it is one of the

best that can be used, to do much work by a given power: It gives
no shock to the water; which, when once in motion, continues to
rise, and escapes when arrived at it’s proper height: and, being
spread over a large surface, no part of it is raised higher than
enough. The perfection of the Machine depends on a due relation
between the centrifugal force, and the sine of the angle, which the
threads of the screw make with the horizon; and this may be
modified by the diameter of the wheels i k, as compared with that of
the screws A B.
The figures 2 and 3, are two views of the upper part of the Machine.
They shew, and mark with the same letters, the cross bar a b, the
inside of the screws, and the circular plates o p, together with the
circular conducting plate of which q q, fig. 1, is the section. Fig. 3
shews the fixed wheel m n, the two screw-wheels i k, the cross piece
a b, and under them the plates o p of the 1st. and 2d. figure.
One other object claims our attention: The threads of the screws
(whether more or less numerous) should each be furnished with a
valve at bottom: that the water may not run out when the Machine
ceases working.
 OF

A FORGING MACHINE,
For Bar Iron, Steel, &c. square or figured.

This Machine acts by pressure instead of percussion. But this

pressure is so instantaneous as to resemble a blow, and so often
repeated as to produce a considerable effect in a short time. The
means are represented in fig. 4 of Plate 25.

There, A is a mass of metal answering the purpose of an anvil, but

having two surfaces, situated at or nearly at right angles to each
other, on which the metal is alternately struck or compressed. The
two sides of this mass A, are perforated by two holes, properly
bushed, in which turn the crank shafts B, C: the latter furnished with
the bevil wheels D, E, which geer into and receive motion from two
equal bevil wheels F, G, fixed on the main shaft H I, and to which
the power is applied. It is thus evident that the two crank shafts B,
C, will make the same number of revolutions; and that if one of the
rollers K, L, is placed on the excentric arm of one shaft, and the
other roller on the other (their position being as in the figure) that
then the rollers K L will impinge alternately on any bar, held in the
angle M, and forge or extend it, and finally leave it reduced to the
same dimensions, in it’s whole length, if, by hand or proper
machinery, the bar has been drawn or pushed along the angle M, in
a manner analogous to this motion at the tilt hammer. It is also
clear, that the size of the bar will be determined on a given Machine,
by the diameters of the rollers K L, compared with the distance of
the shafts from the angle M of the anvil.
It may be of use to observe, that the effect of this Machine is not
confined to square bars: since with unequal rollers K L, it will
produce flat bars; and with rollers properly grooved, (the piece M
being formed accordingly) it will produce round iron or steel of
better texture (I presume) than when taken from the slitting-mill,
and merely passed through grooved rollers. I expect, at all events, a
rapid effect, from four or five hundred turns of the cranks per
minute.
It will occur to every mechanical reader, that the mass M, which is
tempered and adjusted to the principal anvil A, may be still more
varied in form, so as to give other results besides those above
anticipated. Nor need it be said, that the shafts B C might run in
steps capable of being screwed up to their work, even during the
process, should any such motion be expedient. These are details I
do not wish to dwell on in these descriptions—where I endeavour to
make known general and essential properties, leaving particular
views and cases to my reflecting readers.
 OF

A RECIPROCATING HORSE
WHEEL,
For Mines, Mangles, &c.

I believe there is no better floor for a working horse to tread on,

than a plane of wood—on condition, of the horse being rough shod:
I speak however, on recollection of many years’ standing. I then felt
persuaded that a horse wastes less effort by travelling on this floor
than on any other; which is one of my reasons for the adoption of
the present Machine. It consists (Plate 26, fig. 1,) of a wheel A B, on
which the horse walks, as indicated by the sketch of him given in the
figure. Besides this, he is placed between two shafts C D, affixed to
the lever E F, the latter carrying round with it, at intervals, the drum
G, whose office it is to raise the weight I, whatever kind of
resistance that weight represents. This lever runs by means of it’s
cannon L, on a round part of the shaft common to it and to the
drum G. Moreover, there is a second drum H, destined to raise the
weight K, whatever kind of resistance that represents. Both the
drums, G and H, turn on round parts of the main shaft M, but are
alternately connected with it—first, the drum G, by the rising of the
bolt a into it; and secondly, the drum H, by the falling of the cross
piece b c, between the studs e d affixed to it. Now, this cross piece b
c, is part of a T-formed bar, that penetrates the centre of the shaft
as low as f, where it rests on a transverse lever f g, connected to the
right with the bolt a above mentioned, and forming a branch of the
bent lever f g h, which works the bolt h i under the wheel. In the
present state of things, if the horse steps forward, he draws the
shafts C D, round the common centre; for the wheel is immoveable
by means of the bolt i, which takes against some fixed object at k:
and thus will the weight I be raised. And when this motion is
achieved, the handle o is raised a few inches, which brings it into
contact with the obstacle p, and puts a stop to that motion of the
lever E F. At the same time the bolt a, is drawn out of the drum G,
and the cross piece b c is let down between the studs of the drum
H, while, by the bent lever f g h, the bolt h i, which held the wheel,
is drawn back, and then the horse, instead of progressing round the
centre of the wheel, is himself brought locally, to a stand; and
without even knowing it, (for he is blinded) he now treads round the
wheel in a backward direction, and raises the weight K, while the
drum G permits the weight I to descend by the uncoiling of the rope,
till this operation has likewise produced the desired effect—when
things are again placed in the state first observed. One thing
remains to be noticed: It is, that both these motions might have
been produced by acting from a fixed point on the central bar b c f,
through the upper gudgeon of the shaft, instead of using the handle
o, as before directed. It is even easy to conceive how the Machine
may itself be made to perform these changes, and thus to produce
the whole effect without any personal care or attendance.
 OF

AN EXPANDING VESSEL,
For Steam Engines, Pumps, Blowing Machines,
&c.

It is one of the simplest and most perfect operations of the

mechanic art, to form a flat surface: witness the process of grinding
looking glasses, and forming one plane from another. Nor is it,
necessarily, more difficult to place two surfaces parallel to each
other, by means of three or more pillars with proper shoulders, or
counternuts against which to screw the plates from behind. It is
therefore easy to compose an expanding and contracting vessel, that
shall become a mover by the force of any fluid, elastic or not, or
shall act as a water or air pump, when driven by a convenient
power; or both together, when this combination may be desirable.
Thus, in Plate 26, fig. 2 and 3, A B C D is a box with four sides and
four jointed angles—which, if one of it’s sides, D A, be fixed to a
given position in the cage or frame E F G H, will expand or contract
according as the sides A B and D C shall rise toward the
perpendicular, or fall toward the horizontal position. The dotted lines
A 2, A 4, A 6, &c. shew that the successive capacities included in the
vessel, are respectively as the sines of the angles which those sides
A B and D C make with the horizon; so that, although this device
furnishes an unequable power, yet it is equable enough for many
purposes in the first few divisions D 3, D 5, &c. and might be
altogether equalized in it’s effect if necessary. Let us suppose then,
that the aperture 8, brings steam into this vessel: The lid B C will
rise to 6, 7, when, if the pipe 9, communicating with a condenser, be
opened, the steam in the vessel will rush thither and be destroyed:
when the atmosphere will press on the lid B C, and cause the vessel
to collapse with a power proportionate to that area; for the sloping
and parallel sides A B and C D counterpoise each other; where note,
on occasion of the pressure which I am now speaking of, that the
ribs or bars L M, are used to strengthen the sides of the vessel, and
thus prevent it’s fracture under this pressure.
From this manner of making these expanding vessels, it follows
among other things, that if the frame E F G H were surrounded with
wood or any non-conducting substance, and made to communicate
with a warm close room, the atmosphere thus acting on the vessel
would not cool it, and that therefore, an atmospheric engine, would,
in this respect, be as good as a steam-acting one. But steam might
be introduced into this outer case, and act as a spring to reciprocate
the internal effect of the same agent.
The third figure of Plate 26, offers an end view of this cage or frame,
shewing the expanding vessel at B C A D, where the strengthening
ribs of fig. 2 are seen endwise at 1, 3, 5, 7, &c. and moreover, F G
and H are the pillars or cross bars by which the parallelism of the
two end plates is effected and secured.
There remains an important subject to be considered: How to make
the corner joints D C, and the end joints steam or water-tight as
required. The small figure 4 answers the question as far as water is
concerned. A is a strip of leather screwed more or less near to the
edges of two contiguous sides of the vessel, so as to cover the joint
or hinge, and make it water tight whether the pressure come from
within or without. This figure also shews the grooves which receive
the stuffing to close the ends of the vessel, by sliding against the
plates or cheeks E F, &c. fig. 2. The several members of the corner
joints themselves should be well fitted into each other: so indeed as
almost to close the vessel without any stuffing. Nor need we in all
cases be anxious about this stuffing; for I think it very possible to
make this joint close enough for pumping or blowing without any
such provision. I observe, however, that the leather A, fig. 4, might
give place to a strip of thin metal, bent into the same form, (or
nearly so) the elasticity of which would leave play enough for the
joints, on the supposition of working only with a moderate degree of
motion in the said joints.
I should not have given this idea so much attention, had I merely
wished to use it where the cylinder-motion now applies: But my
present views go further. I foresee the use of this Machine for very
low pressures—and in very large dimensions; and I can conceive a
proportion between it’s length and height, that shall as it were annul
the effects of friction and leakage, compared with those of the
cylinder-formed piston. But I do not undertake, or hardly wish now,
to exhaust this subject: being more anxious to deliver the idea to my
readers, than to announce all I intend to undertake by it’s means. I
shall, therefore, merely finish the description of the other figures 5
and 6 of this Plate. The first, is a small hand pump on this principle,
having a suction pipe A, and a rising pipe B, both having proper
valves and opening into the expanding vessel, as worked by the
handle C, much in the manner of a common pump. It will therefore
act by it’s expansive and contractile properties; and have one good
quality we should seek in vain elsewhere—It will begin the motion of
the water with a softness unknown in the use of pumps in general.

In fine, the sixth figure shews a System of this kind applied to the
two objects, of giving power, and using it. The vessel A B, receives
the power from steam or any other agent; and the vessel C blows a
fire, raises water, or does any analogous work, without requiring any
other parts than those here displayed.
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