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Applied Epidemiologic Principles and Concepts

This book provides practical knowledge to clinicians and biomedical research-

ers using biological and biochemical specimen/samples in order to understand
health and disease processes at cellular, clinical, and population levels. The
concepts and techniques provided will help researchers design and conduct
studies, then translate data from bench to clinics in an attempt to improve the
health of patients and populations. This book presents the extreme complex-
ity of epidemiologic research in a concise manner that will address the issue
of confounders, thus allowing for more valid inferences and yielding results
that are more reliable and accurate.

Laurens Holmes Jr. was trained in internal medicine, specializing in immu-

nology and infectious diseases prior to his expertise in epidemiology-with-
biostatistics. Over the past two decades, Dr. Holmes had been working in
cancer epidemiology, control, and prevention. His involvement in chronic
disease epidemiology, control, and prevention includes signal amplification
and stratification in risk modeling and health disparities in hypertension, and
diabetes mellitus with large legacy (preexisting U.S. National Health Statistics
Center) data.
http://taylorandfrancis.com
Applied Epidemiologic Principles and
Concepts
Clinicians’ Guide to Study Design and Conduct

Laurens Holmes Jr., MD, DrPH

First published 2018
by Routledge
711 Third Avenue, New York, NY 10017

and by Routledge
2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN

Routledge is an imprint of the Taylor & Francis Group, an informa business

© 2018 Taylor & Francis

The right of L. Holmes to be identified as author of this work has been asserted by him in accordance
with sections 77 and 78 of the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by
any electronic, mechanical, or other means, now known or hereafter invented, including photocopying
and recording, or in any information storage or retrieval system, without permission in writing from
the publishers.

Trademark notice: Product or corporate names may be trademarks or registered trademarks, and are
used only for identification and explanation without intent to infringe.

Library of Congress Cataloging‑in‑Publication Data

Names: Holmes, Larry, Jr., 1960- author.

Title: Applied epidemiologic principles and concepts : clinicians’ guide to
study design and conduct / Laurens Holmes Jr.
Description: Abingdon, Oxon ; New York, NY : Routledge, 2018. | Includes
bibliographical references and index.
Identifiers: LCCN 2017018332| ISBN 9781498733786 (hardback) | ISBN
9781315369761 (ebook)
Subjects: | MESH: Epidemiologic Research Design
Classification: LCC RA651 | NLM WA 950 | DDC 614.4072--dc23
LC record available at https://lccn.loc.gov/2017018332

ISBN: 978-1-4987-3378-6 (hbk)

ISBN: 9781315369761 (ebk)
Dedicated to Palmer Beasly, MD, MPH (Dean
Emeritus, UTSPH), and James Steele, DVM, MPH
(Retired Assistant US Surgeon General and Professor
Emeritus, UTSPH), both in memoriam!
http://taylorandfrancis.com
Contents

Foreword xiii
Preface xvii
Acknowledgments xxv
Author xxvii

SECTION I
Basic research design principles and study inference 1

1 Epidemiologic research conceptualization and rationale 3

1.1 Introduction 3
1.2 Structure and function of research 4
1.3 Objective of study / research purpose 7
1.4 Research questions and study hypotheses 9
1.5 Primary versus secondary outcomes 12
1.6 Study subjects 19
1.7 Sampling 19
1.8 Generalization 21
1.9 Sample size and power estimations 22
1.10 Summary 23
Questions for discussion 24
References 24

2 Clinical research proposal development and protocol 27

2.1 Introduction 27
2.2 Study conceptualization 28
2.3 Research question 32
2.4 Study background 34
2.5 Protocol implementation 36
viii Contents
2.6 Data collection, management, and analysis 37
2.7 Summary 46
Questions for discussion 47
References 48

3 Epidemiologic design challenges: Confounding and effect

measure modifier 49
3.1 Introduction 49
3.2 Confounding, covariates, and mediation 50
3.3 Assessment for confounding 51
3.4 Confounding, covariates, and mediation 54
3.5 Types of confounding 55
3.6 Confounding and biased estimate 58
3.7 Effect measure modifier 60
3.8 Interaction: Statistical versus biologic 63
3.9 Summary 68
Questions for discussion 69
References 70

4 Epidemiologic case ascertainment: Disease screening

and diagnosis 71
4.1 Introduction 71
4.2 Screening (detection) and diagnostic (confirmation) tests 71
4.3 Disease screening: Principles, advantages, and limitations 78
4.4 Balancing benefits and harmful effects in medicine 84
4.5 Summary 86
Questions for discussion 87
References 88

SECTION II
Epidemiologic concepts and methods 91

5 Epidemiology, historical context, and measures of disease

occurrence and association 93
5.1 Introduction 93
5.2 Epidemiology, clinical medicine, and public health research 97
5.3 The history and modern concept of epidemiology 99
5.4 Models of disease causation 99
5.5 Measures of disease frequency, occurrence, and association 101
5.6 Measures of disease association or effect 110
 Contents ix
5.7 Measures of disease comparison 114
5.8 Sources of epidemiologic data 117
5.9 Summary 117
Questions for discussion 119
References 120

6 Epidemiologic study designs: Overview 121

6.1 Introduction 121
6.2 Nonexperimental versus experimental design 125
6.3 Descriptive and analytic epidemiology 129
6.4 Summary 130
Questions for discussion 130
References 131

7 Ecologic studies: Design, conduct, and interpretation 133

7.1 Introduction 133
7.2 Ecologic studies: Description 133
7.3 Statistical analysis in ecologic design 137
7.4 Ecologic evidence: Association or causation? 138
7.5 Limitations of ecologic study design 138
7.6 Summary 140
Questions for discussion 141
References 142

8 Case-control studies: Design, conduct, and interpretation 143

8.1 Introduction 143
8.2 Basis of case-control design 146
8.3 Variance of case-control design 152
8.4 Scientific reporting in case-control studies:
Methods and results 156
8.5 Summary 160
Questions for discussion 161
References 162

9 Cross-sectional studies: Design, conduct, and interpretation 163

9.1 Introduction 163
9.2 Summary 170
Questions for discussion 172
References 173
x Contents
10 Cohort studies: Design, conduct, and interpretation 175
10.1 Introduction 175
10.2 Cohort designs 178
10.3 Rate ratio estimation in cohort study 198
10.4 Summary 200
Questions for discussion 202
References 202

11 Clinical trials (human experimental designs) 205

11.1 Introduction 205
11.2 Phases of CTs 208
11.3 Types of CT designs and statistical inference 212
11.4 Elements of a CT 214
11.5 Conceptualization and conduct of a CT 214
11.6 Example of a CT 217
11.7 Summary 223
Questions for discussion 224
References 225

12 Causal inference in clinical research and quantitative evidence

synthesis 227
12.1 Introduction 227
12.2 Critique of randomized clinical trials 229
12.3 Special consideration: Critical appraisal of public health /
epidemiologic research 239
12.4 Quantitative evidence synthesis (QES) applied meta-analysis 244
12.5 Statistical / analytic methods 246
12.6 Fixed effects model: Mantel–Haenszel and Peto 246
12.7 Random effects models: DerSimonian–Laird 247
12.8 Random error and precision 252
12.9 Rothman’s component cause model (causal pies) 256
12.10 Summary 260
Questions for discussion 261
References 262
 Contents xi
SECTION III
Perspectives, challenges, and future of epidemiology 263

13 Perspectives, challenges, and future of epidemiology 265

13.1 Introduction 265
13.2 Clinical epidemiology 267
13.3 Infectious disease epidemiology 268
13.4 Molecular and genetic epidemiology 269
13.5 Cancer epidemiology 271
13.6 CD and cardiovascular epidemiology 273
13.7 Epidemiology and health policy formulation 274
13.8 Summary 280
Questions for discussion 281
References 283

14 Health and healthcare policies: Role of epidemiology 285

14.1 Introduction 285
14.2 Health policy 287
14.3 Evidence-based epidemiology and “big data” practice 288
14.4 Health policy formulation: Evidence, politics, and ideology 289
14.5 Decision-making (policy): Legislation, budget and resources
allocation, and jurisdiction of agencies 293
14.6 Decision-making (management): Effectiveness, efficacy,
training, planning, compliance, quality assurance, programming 294
14.7 Summary 295
Questions for discussion 296
References 296

15 Consequentialist epidemiology and translational research

implication 297
15.1 Introduction 297
15.2 Consequentialist science 298
15.3 Incomplete and inconsistent clinical findings 300
15.4 Consequentialist epidemiology: Methods 300
15.5 Addressing accountability: Sampling and confounding,
adequate modeling 301
15.6 Translational epidemiology (TransEpi): Consequential
or traditional 302
15.7 Summary 304
Questions for discussion 305
References 305

Index 307
Foreword

Clinical medicine and surgery had evolved from the observation of individual
patients to a group of patients and currently the examination of “big data”
for clinical decision-making in improving care of our current and prospective
patients. With this dynamic evolution comes challenges in design and appro-
priate interpretation of information generated from these large legacy data
assessments. Specifically, for clinical research to benefit from the evolving
technology in big data approach, clinicians and those working with patients
to improve their care need to be properly informed on design, conduct, analy-
sis, and interpretation of information from big data assessment.
Medicine and surgery continue to make advances by means of evidence
judged to be objectively drawn from the care of individual patients. The natu-
ral observation of individuals remains the basis for our researchable ques-
tions’ formulation and the subsequent hypothesis testing. The effectiveness
of evidence-based medicine or surgery is dependent on how critical we are in
evaluating evidence in order to inform our practice. However, these evalua-
tions, no matter how objective, are never absolute; rather, they are probabilis-
tic, as we will never know with absolute certainty how to treat a future patient
who was not a part of our study. Despite the obstacles facing us today in
attempting to provide an objective evaluation of our patients, since all of our
decisions are based on judgment of some evidence, we have progressed from
relying on expert opinion to the body of evidence accumulated from random-
ized, controlled clinical trials, as well as cohort investigations, prospective and
retrospective.
Conducting a clinical trial yields more reliable and valid evidence from the
data relative to nonexperimental or observational designs; however, although
termed the gold standard, its validity depends on how well it is designed and
conducted prior to outcome data collection, analysis, results, interpretation,
and dissemination. The designs and techniques used to draw statistical infer-
ences are often beyond the average clinician’s understanding. A text that
brings study conceptualization, hypothesis formulation, design, conduct, and
analysis and interpretation of the results is long overdue and highly antici-
pated. Epidemiology is involved with design process, which is essential, since
xiv Foreword
no amount of statistical modeling, no matter how sophisticated, can remove
the error of design.
The text Applied Epidemiologic Principles and Concepts has filled this gap,
not only in the way complex designs are explained but in the simplification of
statistical concepts that had rarely been explained in such a way before. This
text has been prepared intentionally to include rudimentary level information,
so as to benefit clinicians who lack a sophisticated mathematical background
or previous advanced knowledge of epidemiology, as well as other research-
ers who may want to conduct clinical research and consumers of research
products, who may benefit from the design process explained in this book. It
is with this expectation and enthusiasm that we recommend this text to clini-
cians in all fields of clinical, biomedical, and population-based research. The
examples provided by the author to simplify designs and research methods are
familiar to surgeons, as well as to clinicians in other specialties of medicine.
Although statistical inference is essential in our application of the research
findings to clinical decision-making regarding the care of our patients, it
alone, without clinical relevance or importance, can be very misleading or
even meaningless. The author has attempted to deemphasize p value in the
interpretation of epidemiologic or clinical research findings by stressing the
importance of effect size and confidence intervals, which allow for the quan-
tification of evidence and precision, respectively. For example, a large study,
due to a large sample size as big data that minimizes variability, may show a
statistically significant difference which, in reality, the effect size is too insig-
nificant to warrant any clinical importance. In contrast, the results of a small
study, such as is frequently seen in clinical trials or surgical research, may
have a large effect on clinical relevance but not be statistically significant at
(p > 0.05). Thus, without considering the magnitude of the effect size with
the confidence interval, we tend to regard these studies as negative findings,
which is erroneous, since absence of evidence, based simply on an arbitrary
significance level of 5%, does not necessarily mean evidence of absence.1 In
effect, clinical research results cannot be adequately interpreted without con-
sidering the biologic and clinical significance of the data before the statistical
stability of the findings (p value and 95% confidence interval), since p value,
as observed by the authors, merely reflects the size of the study and not the
measure of evidence.
In recommending this text, it is our hope that this book will benefit cli-
nicians, research fellows, clinical fellows, graduate interns, doctoral, post-
doctoral students in medical and clinical settings, nurses, clinical research
coordinators, physical therapists, and all those involved in designing and
conducting clinical research and analyzing research data for statistical and
clinical relevance. Convincingly, knowledge gained from this text will lead to
improvement of patient care through well-conceptualized research. Therefore,
with the knowledge that no book is complete, no matter its content or volume,
especially a book of this nature, which is prepared to guide clinicians and
 Foreword xv
others involved in clinical and medical research on design, conduct, analysis,
and interpretation of findings, we contend that this book will benefit clini-
cians and others who are interested in applying appropriate design to research
conduct, analysis, and interpretation of findings.
Finally, we are optimistic that this book will bridge the gap between
knowledge and practice of clinical research, especially for clinicians in a busy
practice who are passionate about making a difference in their patients’ care
through research and education.

Kirk Dabney, MD, MHCDS

Associate Director
Cerebral Palsy Program
and Clinical Director
Health Equity & Inclusion Office
Nemours/A.I. duPont Hospital for Children
Wilmington, Delaware

Richard Bowen, MD
Former Chairman
Orthopedic Department
A.I. duPont Hospital for Children
Wilmington, Delaware

1. D. G. Altman and J. M. Bland, “Absence of Evidence Is Not Evidence of Absence,”

BMJ 311 (1995): 485.
http://taylorandfrancis.com
Preface

We often conceive of epidemiology in either simplistic or complex terms, and

neither of these is accurate. To illustrate this, complexities in epidemiology
could be achieved by considering a study to determine the correlation between
serum lipid profile as total cholesterol, high-density lipoprotein, low-density
lipoprotein, triglycerides, and total body fatness or obesity measured by body
mass index (BMI) in children. Two laboratories measured serum lipid profile
and one observed a correlation with BMI while the other did not. Which is
the reliable finding? Could these differences reflect interlaboratory variability
or sampling error? To address this question, one needs to examine the context
of blood drawing since fasting blood levels may provide a better indicator of
serum lipid. Epidemiologic studies could be easily derailed given the inability
to identify and address possible confounding. Therefore, understanding the
principles and concepts used in epidemiologic studies’ design and conduct to
answer clinical research questions facilitates accurate and reliable findings in
these areas. Another similar example in a health fair setting involved geogra-
phy and health, termed healthography. The risk of dying in one zip code, A,
was 59.5 per 100,000 and the other zip code, B, was 35.4 per 100,000. There
is a common sense and nonepidemiologic tendency to conclude that there is
increased risk of dying in zip code A. To arrive at such inference, one must
first find out the age distribution of these two zip codes since advancing age
is associated with increased mortality. Indeed, zip code A is comparable to
the US population while zip code B is the Mexican population. These two
examples are indicative of the need to understand epidemiologic concepts
such as confounding by age or effect measure modification prior to undertak-
ing a clinical or translational research.
This textbook describes the basics of research in medical and clinical set-
tings as well as the concepts and application of epidemiologic designs in
research conduct. Design transcends statistical techniques, and no matter
how sophisticated a statistical modeling, errors of design/sampling cannot be
corrected. The author of this textbook has presented a complex field in a very
simplified and reader-friendly manner with the intent that such presentation
will facilitate the understanding of design process and epidemiologic thinking
in clinical research. Additionally, this book provides a very basic explanation
xviii Preface
of how to examine the data collected from research conduct, the possibil-
ity of confounders, and how to address such confounders, thus disentangling
such effects for reliable and valid inference on the association between expo-
sure and the outcome of interest.
Research is presented as an exercise around measurement, with measure-
ment error inevitable in its conduct, hence the inherent uncertainties of all
findings in clinical and medical research. Applied Epidemiologic Principles
and Concepts covers research conceptualization, namely, research objectives,
questions, hypothesis, design, sampling, implementation, data collection,
analysis, results, and interpretation. While the primary focus of epidemiology
is to assess the relationship between exposure (risk or predisposing factor)
and outcome (disease or health-related event), causal association is presented
in a simplified manner, including the role of quantitative evidence synthe-
sis (QES) in causal inference. Epidemiology has evolved over the past three
decades, resulting in several fields being developed. This text presents in brief
the perspectives and future of epidemiology in the era of the molecular basis
of medicine, big data, “3 Ts,” and systems science. Epidemiologic evidence is
more reliable if conceptualized and conducted within the context of trans-
lational, transdisciplinary, and team science. With molecular epidemiology,
we are better equipped with tools to identify molecular, genetic, and cellular
indicators of risk as well as biologic alterations in the early stages of disease,
and with 3 Ts and systems science, we are more capable of providing more
accurate and reliable inference on causality and outcomes research. Further,
the author argues that unless sampling error and confounding are identified
and addressed, clinical and translational research findings will remain largely
inconsistent, implying inconsequential epidemiology. Epidemiology is further
challenged in creating a meaningful collegiality in the process of evidence
discovery with the intent to improve population and patient health. Despite
all the efforts of traditional epidemiologic methods and approach today, risk
factors for many diseases and health outcomes are not fully understood. As
a basic science of public health and clinical medicine, and with the ongoing
emphasis on social determinants of health, advanced epidemiologic methods
require team science and translational approach to embrace socio-epigenomics
and genomics in risk identification and risk adapted intervention mapping.
Appropriate knowledge of research conceptualization, design, and statisti-
cal inference is essential for conducting clinical and biomedical research. This
knowledge is acquired through the understanding of nonexperimental and
experimental epidemiologic designs and the choice of the appropriate test
statistic for statistical inference. However, regardless of how sophisticated the
statistical technique employed for statistical inference is, study conceptualiza-
tion and design mainly adequate sampling process are the building blocks
of valid and reliable scientific evidence. Since clinical research is performed
to improve patients’ care, it remains relevant to assess not only the statistical
significance but also the clinical and biologic importance of the findings, for
clinical decision-making in the care of an individual patient. Therefore, the
 Preface xix
aim of this book is to provide clinicians, biomedical researchers, graduate
students in research methodology, students of public health, and all those
involved in clinical/translational research with a simplified but concise over-
view of the principles and practice of epidemiology. In addition, the author
stresses common flaws in the conduct, analysis, and interpretation of epide-
miologic study.
Valid and reliable scientific research is that which considers the following
elements in arriving at the truth from the data, namely, biological relevance,
clinical importance, and statistical stability and precision (statistical inference
based on the p value and the 90%, 95%, and 99% confidence interval).
The interpretation of results of new research must rely on factual associa-
tion or effect and the alternative explanation, namely, systematic error, ran-
dom error (precision), confounding, and effect measure modifier. Therefore,
unless these perspectives are disentangled, the results from any given research
cannot be considered valid and reliable. However, even with this disentangle-
ment, all study findings remain inconclusive with some degree of uncertainty,
hence the random error quantification (p value).
This book presents a comprehensive guide on how to conduct clinical and
medical research—mainly, research question formulation, study implementa-
tion, hypothesis testing using appropriate test statistics to analyze the data,
and results interpretation. In so doing, it attempts to illustrate the basic con-
cepts used in study conceptualization, epidemiologic design, and appropri-
ate test statistics for statistical inference from the data. Therefore, although
statistical inference is emphasized throughout the presentation in this text,
equal emphasis is placed on clinical relevance or importance and biological
relevance in the interpretation of the study results.
Specifically, this book describes in basic terms and concepts how to con-
duct clinical and medical research using epidemiologic designs. The author
presents epidemiology as the main profession in the transdisciplinary and
team science approaches to the understanding of complex ecologic model
of disease and health. Clinicians, even those without preliminary or infantile
knowledge of epidemiologic designs, could benefit immensely on what, when,
where, who, and how studies are conceptualized, data collected as planned
with the scale of measurement of the outcome and independent variables,
data edited, cleaned and processed prior to analysis, appropriate analysis
based on statistical assumptions and rationale, results tabulation for scien-
tific appraisal, and results interpretation and inference. Unlike most epide-
miologic texts, this is one of the few books that attempts to simplify complex
epidemiologic methods for users of epidemiologic research namely clinicians.
Additionally, it is rare to find an epidemiology textbook with integration of
basic research methodology into epidemiologic designs. Finally, research
innovation and the current challenges of epidemiology are presented in this
book to reflect the currency of the materials and the approach.
A study could be statistically significant but biologically and clinically
irrelevant, since the statistical stability of a study does not rule out bias and
xx Preface
confounding. The p value is deemphasized, while the use of effect size or mag-
nitude and confidence intervals in the interpretation of results for application
in clinical decision-making is recommended. The use of p value as the mea-
sure of evidence could lead to an erroneous interpretation of the effectiveness
of a treatment. For example, studies with large sample sizes and very little
or insignificant effects of no clinical importance may be statistically signifi-
cant, while studies with small samples though a large magnitude of effects are
labeled “negative result.”1 Such results are due to low statistical power and
increasing variability, hence the inability to pass the arbitrary litmus test of
the 5% significance level.

Epidemiology Conceptualized
Epidemiologic investigation and practice, as old as the history of modern
medicine, date back to Hippocrates (circa 2,400 years ago). In recommending
the appropriate practice of medicine, Hippocrates appealed to the physicians’
ability to understand the role of environmental factors in predisposition
to disease and health in the community. During the Middle Ages and the
Renaissance, epidemiologic principles continued to influence the practice of
medicine, as demonstrated in De Morbis Artificum (1713) by Ramazinni and
the works on scrotal cancer in relation to chimney sweeps by Percival Pott in
1775.
With the works of John Snow, a British physician (1854), on cholera mor-
tality in London, the era of scientific epidemiology began. By examining the
distribution/pattern of mortality and cholera in London, Snow postulated
that cholera was caused by contaminated water.

Epidemiology Today
There are several definitions of epidemiology, but a practical definition is nec-
essary for the understanding of this human science. Epidemiology is the basic
science of public health. The objective of this discipline is to assess the dis-
tribution and determinants of disease, disabilities, injuries, natural disasters
(tsunamis, hurricanes, tornados, and earthquakes) and health-related events
at the population level. Epidemiologic investigation or research focuses on a
specific population. The basic issue is to assess the groups of people at higher
risk: women, children, men, pregnant women, teenagers, whites, African
Americans, Hispanics, Asians, poor, affluent, gay, lesbians, transgender, mar-
ried, single, older individuals, obese/overweight etc. Epidemiology also exam-
ines the frequency of the disease or the event of interest changes over time.
In addition, epidemiology examines the variation of the disease of interest
from place to place. Simply, descriptive epidemiology attempts to address
the distribution of disease with respect to “who,” “when,” and “where.” For
 Preface xxi
example, cancer epidemiologists attempt to describe the occurrence of pros-
tate cancer by observing the differences in populations due to age, socioeco-
nomic status, occupation, geographic locale, race/ethnicity, etc. Epidemiology
also attempts to address the association between the disease (outcome) and
exposure (risk factor). For example, why are some men at high risk for pros-
tate cancer? Does race/ethnicity increase the risk for prostate cancer? Simply,
is the association causal or spurious? This process involves the effort to deter-
mine whether a factor (exposure) is associated with the disease (outcome). In
the example with prostate cancer, such exposure includes a high-fat diet, race/
ethnicity, advancing age, pesticides, family history of prostate cancer, and so
on. Whether or not the association is factual or a result of chance remains
the focus of epidemiologic research. The questions to be raised are as follows:
Is prostate cancer associated with pesticides? Does pesticide cause prostate
cancer?
Epidemiology often goes beyond disease-exposure association or relation-
ship to establish causal association (association to causation). In this process
of causal inference, it depends on certain criteria, one of which is the strength
or magnitude of association, leading to the recommendation of preventive
measures. However, complete knowledge of the causal mechanism is not nec-
essary prior to preventive measures for disease control. Further, findings from
epidemiologic research facilitate the prioritization of health issues and the
development and implementation of intervention programs for disease con-
trol and health promotion.
This book is conceptually organized in three sections. Section I deals with
research methods and epidemiologic complexities in terms of design and anal-
ysis, Section II deals with epidemiologic designs, as well as causal inference,
while Section III delves into perspectives, epidemiologic challenges, and spe-
cial topics in epidemiology, namely, epidemiologic tree, challenges, emerging
fields, consequentialist perspective of epidemiology and epidemiologic role
in health and healthcare policy formulation. Throughout this book, attempts
are made to describe the research methods and nonexperimental as well as
experimental designs. Section I comprises research methods and design com-
plexities with an attempt to describe the following:

• Research objectives and purposes

• Research questions
• Hypothesis statements: null and alternative
• Rationales for research, clinical reasoning, and diagnostic tests
• Study conceptualization and conduct—research question, data collec-
tion, data management, hypothesis testing, data analysis
• Confounding
• Effect measure modification
• Diagnostic and screening test
xxii Preface
Section II comprises the epidemiologic study designs with an attempt to
describe the basic notion of epidemiology and the designs used in clinical
research:

• The notion of epidemiology and the measures of disease occurrence/

frequency and the measure of disease association/effect
• Ecologic studies
• Cross-sectional designs
• Case-control studies
• Cohort studies: prospective, retrospective, and ambidirectional
• Clinical trials or experimental designs
• QES, meta-analysis, scientific study appraisal, and causal inference

Section III consists of perspectives, challenges, future, and special topics in

epidemiology in illustrating the purposive role of epidemiology in facilitat-
ing the goal of public health, mainly disease control and health promotion.
Additionally, this section presents the integrative dimension of epidemiology.

• Epidemiologic perspectives: advances, challenges, emerging fields, and

the future
• Consequentialist epidemiology
• Role of epidemiology in health and healthcare policy formulation

Section I has five chapters. The first two chapters deal with the basic
descriptions of scientific research at the clinical and population levels and
how the knowledge gained from the population could be applied to the under-
standing of individual patients in the future. The attempt is made in these
chapters to discuss clinical reasoning and the use of diagnostic tests (sensitiv-
ity and specificity) in clinical decision-making. The notions, numbers needed
to treat, and numbers needed to harm are discussed later in the chapter on
causal inference. These chapters delve into clinical research conceptualization,
design involving subject recruitment, variable ascertainment, data collection,
data management, data analysis, and the outline of the research proposal.
In Section II, epidemiologic principles and methods are presented with
the intent to stress the importance of a careful design in conducting clinical
research. Epidemiology remains the basic science of clinical medicine and
public health that deals with disease, disabilities, injury, and health-related
event distributions and determinants and the application of this knowledge
to the control and prevention of disease, disabilities, injuries, and related
health events at the population level. Depending on the research question and
whether or not the outcome (disease or event of interest) has occurred prior to
the commencement of the study or the investigator assigns subjects to treat-
ment or control, an appropriate design is selected for the clinical research. The
measures of effects or point estimates are discussed with concrete examples to
illustrate the application of epidemiologic principles in arriving at a reliable
 Preface xxiii
and valid result. Designs are illustrated with flow charts, figures, and boxes for
distinctions and similarities. The hierarchy of study design is demonstrated
with randomized clinical trial (RCT) and the associated meta-analysis and
QES as the design that yields the most reliable and valid evidence from data.
Although RCTs are considered the “gold standard” of clinical research, it is
sometimes not feasible to use this design because of ethical considerations,
hence the alternative need for prospective cohort design.
Interpreting research findings is equally as essential as conducting the
study itself. Interpretation of research findings must be informative and con-
structive in order to identify future research needs. A research result cannot
be considered valid unless we disentangle the role of bias and confounding
from a statistically significant finding, as a result can be statistically signifi-
cant and yet driven by measurement, selection, and information bias as well
as confounding. While my background in basic medical sciences and clini-
cal medicine (internal medicine) allows me to appreciate the importance of
­biologic and clinical relevance in the interpretation of research findings, bio-
statisticians without similar training must look beyond random variation
(p value and confidence interval) in the interpretation and utilization of clini-
cal and translational research findings. Therefore, quantifying the random
error with p value (a meaningful null hypothesis with a strong case against
the null hypothesis requires the use of significance level) without a ­confidence
interval deprives the reader of the ability to assess the clinical importance
of the range of values in the interval. Using Fisher’s arbitrary p value c­ utoff
point for type I error (alpha level) tolerance, a p value of 0.05 need not provide
strong evidence against the null hypothesis, but p less than 0.0001 does.2 The
precise p value should be presented, without reference to arbitrary thresh-
olds. Therefore, results of clinical and translational research should not be
presented as “significant” or “nonsignificant” but should be interpreted in
the context of the type of study and other available evidence. Second, sys-
tematic error and confounding should always be considered for findings with
low p values, as well as the potentials for effect measure modifier (if any) in
the explanation of the results. Neyman and Pearson describe their accurate
observation:

No test based upon a theory of probability can by itself provide any

valuable evidence of the truth or falsehood of a hypothesis. But we may
look at the puvrpose of tests from another viewpoint. Without hoping to
know whether each separate hypothesis is true or false, we may search for
rules to govern our behavior with regard to them, in following which we
insure that, in the long run of experience, we shall not often be wrong.3

This text is expected to provide practical knowledge to clinicians and trans-

lationists, implying all researchers using biological and biochemical specimen
or samples in an attempt to understand health and diseases processes at cellu-
lar (preclinical and laboratory), clinical, and population levels, additionally all
xxiv Preface
those who translate such data from bench to clinics in an attempt to improve
the health and well-being of the patients they see.
Specifically, this book describes in basic terms and concepts how to con-
duct clinical research using epidemiologic designs. The author presents epi-
demiology as the main discipline so to speak in the transdisciplinary and
translational approaches to the understanding of complex ecologic model
of disease and health. Clinicians, even those without preliminary or those
with infantile knowledge of epidemiologic designs, could benefit immensely
from this text, namely, on what, when, where, who, and how studies are con-
ceptualized; data collected as planned with the scale of measurement of the
outcome and independent variables; data edited, cleaned, and processed prior
to analysis; appropriate analysis based on statistical assumptions and ratio-
nale; results tabulation for scientific appraisal; and result interpretation and
inference. Unlike most epidemiologic texts, this is one of the few books that
attempt to simplify complex epidemiologic methods for users of epidemio-
logic research namely clinicians. Additionally, it is extremely rare to access
a book with integration of basic research methodology into epidemiologic
designs. Finally, research innovation and the current challenges of epidemiol-
ogy are presented in this book to reflect the currency of the materials and the
approach.
Epidemiology is an ever-changing discipline. The author has consulted
with data judged to be accurate at the moment of the presentation of these
materials for publication. However, due to rapid changes in risk factor identi-
fication and biomarkers of disease, the limitations of human knowledge, and
the possibility of errors, the author wishes to be insulated from any responsi-
bility due to error arising from the use of this text. Since epidemiology is an
inexact science and scientific knowledge is cumulative, indicative of the need
for replication science in our continuous effort to improve health, caution
must be applied in the use and application of the information in this text.
Therefore, readers are advised to consult with other sources of similar data
for the confirmation of the information therein.

1. D. G. Altman and J. M. Bland, “Absence of Evidence Is Not Evidence of Absence,”

BMJ 311 (1995): 485.
2. R. A. Fisher, Statistical Methods and Scientific Inference (London: Collins
Macmillan, 1973).
3. J. Neyman and E. Pearson, “On the Problem of the Most Efficient Tests of
Statistical Hypotheses,” Philos Trans Roy Soc A 231 (1933): 289–337.
Acknowledgments

In preparing this book, so many people contributed directly or indirectly to

the materials provided here. In order to make this book practical, data col-
lected from different studies were used. I wish to express sincere gratitude to
those who permitted the use of their data to illustrate the design techniques
used in this book.
The attempt to create a simplified book in epidemiology remains challeng-
ing because of variability in the epidemiologic reasoning of those who require
such materials. The simplification, so to speak, of the design process in evi-
dence in clinical research came from my interaction with research and clinical
fellows at the Nemours Orthopedic Department, who worked with me and
gave me the reason to write this book. They are Drs. K. Durga, M. Ali, S. Joo,
T. Palocaren, T. Haumont, M.J. Cornes, A. Tahbet, A. Atanda, J. Connor,
M. Oto, M. Kadhim, and A. Karatas. The clinical research fellows and surgical
residents in the orthopedic department also motivated the preparation of this
text. Thank you for your interest in the evidence-based journal club.
My colleagues at the Nemours Orthopedic Department, Nemours Center
for Childhood Cancer Research, and the University of Delaware, College
of Health Sciences, also inspired this preparation via questions on study
design, sample size, and power estimations, p value and confidence interval
(CI) interpretation, and the preference of 95% CI to p value in terms of sta-
tistical stability. They are Drs. Richard Bowen, Kirk Dabney, Suken Shah,
Tariq Rahman, George Dodge, Pete Gabos, Freeman Miller, Richard Kruse,
Nahir Thacker, Kenneth Rogers, William Mackenzie, Sigrid Rajaskaren, Raj
Rajasekaren, Paul Pitel, Jim Richards, and Stephen Stanhope.
I am indebted in a special way to peers in epidemiology and translational
science, namely, Professor Bradley Pollock (UCDavis), Professor Reza Shaker
(MCW), Professor Barry Borman (Massey University, NZ), and Professor
Kenneth Rothman (Boston University), and for those not mentioned here,
for the encouragement to present this material in a special setting, clinical and
translational science environment.
I am unable to express adequately my gratitude to my kids (Maddy,
Mackenzie, Landon, Aiden, and Devin) for their understanding and accep-
tance of the time I spent away from them to work on this book. To my
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 THÉOPHILE GAUTIER

ROMANS
ET CONTES

PARIS

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28, QUAI DU LOUVRE

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ROMANS ET CONTES
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LE CAPITAINE FRACASSE 2 vol.
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ROMANS ET CONTES
 AVATAR
I

Personne ne pouvait rien comprendre à la maladie qui minait

lentement Octave de Saville. Il ne gardait pas le lit et menait son
train de vie ordinaire; jamais une plainte ne sortait de ses lèvres, et
cependant il dépérissait à vue d’œil. Interrogé par les médecins que
le forçaient à consulter la sollicitude de ses parents et de ses amis, il
n’accusait aucune souffrance précise, et la science ne découvrait en
lui nul symptôme alarmant: sa poitrine auscultée rendait un son
favorable, et à peine si l’oreille appliquée sur son cœur y surprenait
quelque battement trop lent ou trop précipité; il ne toussait pas,
n’avait pas la fièvre, mais la vie se retirait de lui et fuyait par une de
ces fentes invisibles dont l’homme est plein, au dire de Térence.
Quelquefois une bizarre syncope le faisait pâlir et froidir comme
un marbre. Pendant une ou deux minutes on eût pu le croire mort;
puis le balancier, arrêté par un doigt mystérieux, n’étant plus retenu,
reprenait son mouvement, et Octave paraissait se réveiller d’un
songe. On l’avait envoyé aux eaux; mais les nymphes thermales ne
purent rien pour lui. Un voyage à Naples ne produisit pas un meilleur
résultat. Ce beau soleil si vanté lui avait semblé noir comme celui de
la gravure d’Albert Durer; la chauve-souris qui porte écrit dans son
aile ce mot, melancholia, fouettait cet azur étincelant de ses
membranes poussiéreuses et voletait entre la lumière et lui; il s’était
senti glacé sur le quai de la Mergellina, où les lazzaroni demi-nus se
cuisent et donnent à leur peau une patine de bronze.
 Il était donc revenu à son petit appartement de la rue Saint-
Lazare et avait repris en apparence ses habitudes anciennes.
Cet appartement était aussi confortablement meublé que peut
l’être une garçonnière. Mais comme un intérieur prend à la longue la
physionomie et peut-être la pensée de celui qui l’habite, le logis
d’Octave s’était peu à peu attristé; le damas des rideaux avait pâli et
ne laissait plus filtrer qu’une lumière grise. Les grands bouquets de
pivoine se flétrissaient sur le fond moins blanc du tapis; l’or des
bordures encadrant quelques aquarelles et quelques esquisses de
maîtres avait lentement rougi sous une implacable poussière; le feu
découragé s’éteignait et fumait au milieu des cendres. La vieille
pendule de Boule incrustée de cuivre et d’écaille verte retenait le
bruit de son tic-tac, et le timbre des heures ennuyées parlait bas
comme on fait dans une chambre de malade; les portes retombaient
silencieuses, et les pas des rares visiteurs s’amortissaient sur la
moquette; le rire s’arrêtait de lui-même en pénétrant dans ces
chambres mornes, froides et obscures, où cependant rien ne
manquait du luxe moderne. Jean, le domestique d’Octave, s’y glissait
comme une ombre, un plumeau sous le bras, un plateau sur la main,
car, impressionné à son insu de la mélancolie du lieu, il avait fini par
perdre sa loquacité.—Aux murailles pendaient en trophée des gants
de boxe, des masques et des fleurets; mais il était facile de voir
qu’on n’y avait pas touché depuis longtemps; des livres pris et jetés
insouciamment traînaient sur tous les meubles, comme si Octave eût
voulu, par cette lecture machinale, endormir une idée fixe. Une lettre
commencée, dont le papier avait jauni, semblait attendre depuis des
mois qu’on l’achevât, et s’étalait comme un muet reproche au milieu
du bureau. Quoique habité, l’appartement paraissait désert. La vie
en était absente, et en y entrant on recevait à la figure cette bouffée
d’air froid qui sort des tombeaux quand on les ouvre.
Dans cette lugubre demeure où jamais une femme n’aventurait le
bout de sa bottine, Octave se trouvait plus à l’aise que partout
ailleurs,—ce silence, cette tristesse et cet abandon lui convenaient;
le joyeux tumulte de la vie l’effarouchait, quoiqu’il fît parfois des
efforts pour s’y mêler; mais il revenait plus sombre des mascarades,
des parties ou des soupers où ses amis l’entraînaient; aussi ne
luttait-il plus contre cette douleur mystérieuse, et laissait-il aller les
jours avec l’indifférence d’un homme qui ne compte pas sur le
lendemain. Il ne formait aucun projet, ne croyant plus à l’avenir, et il
avait tacitement envoyé à Dieu sa démission de la vie, attendant
qu’il l’acceptât. Pourtant, si vous vous imaginiez une figure amaigrie
et creusée, un teint terreux, des membres exténués, un grand
ravage extérieur, vous vous tromperiez; tout au plus apercevrait-on
quelques meurtrissures de bistre sous les paupières, quelques
nuances orangées autour de l’orbite, quelque attendrissement aux
tempes sillonnées de veines bleuâtres. Seulement l’étincelle de l’âme
ne brillait pas dans l’œil, dont la volonté, l’espérance et le désir
s’étaient envolés. Ce regard mort dans ce jeune visage formait un
contraste étrange, et produisait un effet plus pénible que le masque
décharné, aux yeux allumés de fièvre, de la maladie ordinaire.
Octave avait été, avant de languir de la sorte, ce qu’on nomme
un joli garçon, et il l’était encore: d’épais cheveux noirs, aux boucles
abondantes, se massaient, soyeux et lustrés, de chaque côté de ses
tempes; ses yeux longs, veloutés, d’un bleu nocturne, frangés de cils
recourbés, s’allumaient parfois d’une étincelle humide; dans le repos,
et lorsque nulle passion ne les animait, ils se faisaient remarquer par
cette quiétude sereine qu’ont les yeux des Orientaux, lorsqu’à la
porte d’un café de Smyrne ou de Constantinople ils font le kief après
avoir fumé leur narguilhé. Son teint n’avait jamais été coloré, et
ressemblait à ces teints méridionaux d’un blanc olivâtre qui ne
produisent tout leur effet qu’aux lumières; sa main était fine et
délicate, son pied étroit et cambré. Il se mettait bien, sans précéder
la mode ni la suivre en retardataire, et savait à merveille faire valoir
ses avantages naturels. Quoiqu’il n’eût aucune prétention de dandy
ou de gentleman rider, s’il se fût présenté au Jockey-Club, il n’eût
pas été refusé.
Comment se faisait-il que, jeune, beau, riche, avec tant de
raisons d’être heureux, un jeune homme se consumât si
misérablement? Vous allez dire qu’Octave était blasé, que les romans
à la mode du jour lui avaient gâté la cervelle de leurs idées
malsaines, qu’il ne croyait à rien, que de sa jeunesse et de sa
fortune gaspillées en folles orgies il ne lui restait que des dettes;—
toutes ces suppositions manquent de vérité.—Ayant fort peu usé des
plaisirs, Octave ne pouvait en être dégoûté; il n’était ni splénétique,
ni romanesque, ni athée, ni libertin, ni dissipateur; sa vie avait été
jusqu’alors mêlée d’études et de distractions comme celle des autres
jeunes gens; il s’asseyait le matin au cours de la Sorbonne, et le soir
il se plantait sur l’escalier de l’Opéra pour voir s’écouler la cascade
des toilettes. On ne lui connaissait ni fille de marbre ni duchesse, et
il dépensait son revenu sans faire mordre ses fantaisies au capital,—
son notaire l’estimait;—c’était donc un personnage tout uni,
incapable de se jeter au glacier de Manfred ou d’allumer le réchaud
d’Escousse. Quant à la cause de l’état singulier où il se trouvait et
qui mettait en défaut la science de la faculté, nous n’osons l’avouer,
tellement la chose est invraisemblable à Paris, au dix-neuvième
siècle, et nous laissons le soin de la dire à notre héros lui-même.
Comme les médecins ordinaires n’entendaient rien à cette
maladie étrange, car on n’a pas encore disséqué d’âme aux
amphithéâtres d’anatomie, on eut recours en dernier lieu à un
docteur singulier, revenu des Indes après un long séjour, et qui
passait pour opérer des cures merveilleuses.
Octave, pressentant une perspicacité supérieure et capable de
pénétrer son secret, semblait redouter la visite du docteur, et ce ne
fut que sur les instances réitérées de sa mère qu’il consentit à
recevoir M. Balthazar Cherbonneau.
Quand le docteur entra, Octave était à demi couché sur un divan:
un coussin étayait sa tête, un autre lui soutenait le coude, un
troisième lui couvrait les pieds; une gandoura l’enveloppait de ses
plis souples et moelleux; il lisait ou plutôt il tenait un livre, car ses
yeux arrêtés sur une page ne regardaient pas. Sa figure était pâle,
mais, comme nous l’avons dit, ne présentait pas d’altération bien
sensible. Une observation superficielle n’aurait pas cru au danger
chez ce jeune malade, dont le guéridon supportait une boîte à
cigares au lieu des fioles, des lochs, des potions, des tisanes, et
autres pharmacopées de rigueur en pareil cas. Ses traits purs,
quoiqu’un peu fatigués, n’avaient presque rien perdu de leur grâce,
et, sauf l’atonie profonde et l’incurable désespérance de l’œil, Octave
eût semblé jouir d’une santé normale.
Quelque indifférent que fût Octave, l’aspect bizarre du docteur le
frappa. M. Balthazar Cherbonneau avait l’air d’une figure échappée
d’un conte fantastique d’Hoffmann et se promenant dans la réalité
stupéfaite de voir cette création falote. Sa face extrêmement
basanée était comme dévorée par un crâne énorme que la chute des
cheveux faisait paraître plus vaste encore. Ce crâne nu, poli comme
de l’ivoire, avait gardé ses teintes blanches, tandis que le masque,
exposé aux rayons du soleil, s’était revêtu, grâce aux superpositions
des couches du hâle, d’un ton de vieux chêne ou de portrait enfumé.
Les méplats, les cavités et les saillies des os s’y accentuaient si
vigoureusement, que le peu de chair qui les recouvrait ressemblait,
avec ses mille rides fripées, à une peau mouillée appliquée sur une
tête de mort. Les rares poils gris qui flânaient encore sur l’occiput,
massés en trois maigres mèches dont deux se dressaient au-dessus
des oreilles et dont la troisième partait de la nuque pour mourir à la
naissance du front, faisaient regretter l’usage de l’antique perruque à
marteaux ou de la moderne tignasse de chiendent, et couronnaient
d’une façon grotesque cette physionomie de casse-noisettes. Mais ce
qui occupait invinciblement chez le docteur, c’étaient les yeux; au
milieu de ce visage tanné par l’âge, calciné à des cieux
incandescents, usé dans l’étude, où les fatigues de la science et de
la vie s’écrivaient en sillages profonds, en pattes d’oie rayonnantes,
en plis plus pressés que les feuillets d’un livre, étincelaient deux
prunelles d’un bleu de turquoise, d’une limpidité, d’une fraîcheur et
d’une jeunesse inconcevables. Ces étoiles bleues brillaient au fond
d’orbites brunes et de membranes concentriques dont les cercles
fauves rappelaient vaguement les plumes disposées en auréole
autour de la prunelle nyctalope des hiboux. On eût dit que, par
quelque sorcellerie apprise des brahmes et des pandits, le docteur
avait volé des yeux d’enfant et se les était ajustés dans sa face de
cadavre. Chez le vieillard, le regard marquait vingt ans; chez le jeune
homme, il en marquait soixante.
 Le costume était le costume classique du médecin: habit et
pantalon de drap noir, gilet de soie de même couleur, et sur la
chemise un gros diamant, présent de quelque rajah ou de quelque
nabab. Mais ces vêtements flottaient comme s’ils eussent été
accrochés à un portemanteau, et dessinaient des plis
perpendiculaires que les fémurs et les tibias du docteur cassaient en
angles aigus lorsqu’il s’asseyait. Pour produire cette maigreur
phénoménale, le dévorant soleil de l’Inde n’avait pas suffi. Sans
doute Balthazar Cherbonneau s’était soumis, dans quelque but
d’initiation, aux longs jeûnes des fakirs et tenu sur la peau de gazelle
auprès des yoghis entre les quatre réchauds ardents; mais cette
déperdition de substance n’accusait aucun affaiblissement. Des
ligaments solides et tendus sur les mains comme les cordes sur le
manche d’un violon reliaient entre eux les osselets décharnés des
phalanges et les faisaient mouvoir sans trop de grincements.
Le docteur s’assit sur le siége qu’Octave lui désignait de la main à
côté du divan, en faisant des coudes comme un mètre qu’on reploie
et avec des mouvements qui indiquaient l’habitude invétérée de
s’accroupir sur des nattes. Ainsi placé, M. Cherbonneau tournait le
dos à la lumière, qui éclairait en plein le visage de son malade,
situation favorable à l’examen et que prennent volontiers les
observateurs, plus curieux de voir que d’être vus. Quoique la figure
du docteur fût baignée d’ombre et que le haut de son crâne, luisant
et arrondi comme un gigantesque œuf d’autruche, accrochât seul au
passage un rayon du jour, Octave distinguait la scintillation des
étranges prunelles bleues qui semblaient douées d’une lueur propre
comme les corps phosphorescents: il en jaillissait un rayon aigu et
clair que le jeune malade recevait en pleine poitrine avec cette
sensation de picotement et de chaleur produite par l’émétique.
«Eh bien, monsieur, dit le docteur après un moment de silence
pendant lequel il parut résumer les indices reconnus dans son
inspection rapide, je vois déjà qu’il ne s’agit pas avec vous d’un cas
de pathologie vulgaire; vous n’avez aucune de ces maladies
cataloguées, à symptômes bien connus, que le médecin guérit ou
empire; et quand j’aurai causé quelques minutes, je ne vous
demanderai pas du papier pour y tracer une anodine formule du
Codex au bas de laquelle j’apposerai une signature hiéroglyphique et
que votre valet de chambre portera au pharmacien du coin.»
Octave sourit faiblement, comme pour remercier M. Cherbonneau
de lui épargner d’inutiles et fastidieux remèdes.
«Mais, continua le docteur, ne vous réjouissez pas si vite; de ce
que vous n’avez ni hypertrophie du cœur, ni tubercules au poumon,
ni ramollissement de la moelle épinière, ni épanchement séreux au
cerveau, ni fièvre typhoïde ou nerveuse, il ne s’ensuit pas que vous
soyez en bonne santé. Donnez-moi votre main.»
Croyant que M. Cherbonneau allait lui tâter le pouls et
s’attendant à lui voir tirer sa montre à secondes, Octave retroussa la
manche de sa gandoura, mit son poignet à découvert et le tendit
machinalement au docteur. Sans chercher du pouce cette pulsation
rapide ou lente qui indique si l’horloge de la vie est détraquée chez
l’homme, M. Cherbonneau prit dans sa patte brune, dont les doigts
osseux ressemblaient à des pinces de crabe, la main fluette, veinée
et moite du jeune homme; il la palpa, la pétrit, la malaxa en quelque
sorte comme pour se mettre en communication magnétique avec
son sujet. Octave, bien qu’il fût sceptique en médecine, ne pouvait
s’empêcher d’éprouver une certaine émotion anxieuse, car il lui
semblait que le docteur lui soutirait l’âme par cette pression, et le
sang avait tout à fait abandonné ses pommettes.
«Cher monsieur Octave, dit le médecin en laissant aller la main
du jeune homme, votre situation est plus grave que vous ne pensez,
et la science, telle du moins que la pratique la vieille routine
européenne, n’y peut rien: vous n’avez plus la volonté de vivre, et
votre âme se détache insensiblement de votre corps; il n’y a chez
vous ni hypocondrie, ni lypémanie, ni tendance mélancolique au
suicide.—Non!—cas rare et curieux, vous pourriez, si je ne m’y
opposais, mourir sans aucune lésion intérieure ou externe
appréciable. Il était temps de m’appeler, car l’esprit ne tient plus à la
chair que par un fil; mais nous allons y faire un bon nœud.» Et le
docteur se frotta joyeusement les mains en grimaçant un sourire qui
détermina un remous de rides dans les mille plis de sa figure.
 «Monsieur Cherbonneau, je ne sais si vous me guérirez, et, après
tout, je n’en ai nulle envie, mais je dois avouer que vous avez
pénétré du premier coup la cause de l’état mystérieux où je me
trouve. Il me semble que mon corps est devenu perméable, et laisse
échapper mon moi comme un crible l’eau par ses trous. Je me sens
fondre dans le grand tout, et j’ai peine à me distinguer du milieu où
je plonge. La vie dont j’accomplis, autant que possible, la
pantomime habituelle, pour ne pas chagriner mes parents et mes
amis, me paraît si loin de moi, qu’il y a des instants où je me crois
déjà sorti de la sphère humaine: je vais et je viens par les motifs qui
me déterminaient autrefois, et dont l’impulsion mécanique dure
encore, mais sans participer à ce que je fais. Je me mets à table aux
heures ordinaires, et je parais manger et boire, quoique je ne sente
aucun goût aux plats les plus épicés et aux vins les plus forts: la
lumière du soleil me semble pâle comme celle de la lune, et les
bougies ont des flammes noires. J’ai froid aux plus chauds jours de
l’été; parfois il se fait en moi un grand silence comme si mon cœur
ne battait plus et que les rouages intérieurs fussent arrêtés par une
cause inconnue. La mort ne doit pas être différente de cet état si elle
est appréciable pour les défunts.
—Vous avez, reprit le docteur, une impossibilité de vivre
chronique, maladie toute morale et plus fréquente qu’on ne pense.
La pensée est une force qui peut tuer comme l’acide prussique,
comme l’étincelle de la bouteille de Leyde, quoique la trace de ses
ravages ne soit pas saisissable aux faibles moyens d’analyse dont la
science vulgaire dispose. Quel chagrin a enfoncé son bec crochu
dans votre foie? Du haut de quelle ambition secrète êtes-vous
retombé brisé et moulu? Quel désespoir amer ruminez-vous dans
l’immobilité? Est-ce la soif du pouvoir qui vous tourmente? Avez-vous
renoncé volontairement à un but placé hors de la portée humaine?—
Vous êtes bien jeune pour cela.—Une femme vous a-t-elle trompé?
—Non, docteur, répondit Octave, je n’ai pas même eu ce
bonheur.
—Et cependant, reprit M. Balthazar Cherbonneau, je lis dans vos
yeux ternes, dans l’habitude découragée de votre corps, dans le
timbre sourd de votre voix, le titre d’une pièce de Shakspeare aussi
nettement que s’il était estampé en lettres d’or sur le dos d’une
reliure de maroquin.
—Et quelle est cette pièce que je traduis sans le savoir? dit
Octave, dont la curiosité s’éveillait malgré lui.
—Love’s labour’s lost, continua le docteur avec une pureté
d’accent qui trahissait un long séjour dans les possessions anglaises
de l’Inde.
—Cela veut dire, si je ne me trompe, peines d’amour perdues.
—Précisément.»
Octave ne répondit pas; une légère rougeur colora ses joues, et,
pour se donner une contenance, il se mit à jouer avec le gland de sa
cordelière: le docteur avait reployé une de ses jambes sur l’autre, ce
qui produisait l’effet des os en sautoir gravés sur les tombes, et se
tenait le pied avec la main à la mode orientale. Ses yeux bleus se
plongeaient dans les yeux d’Octave et les interrogeaient d’un regard
impérieux et doux.
«Allons, dit M. Balthazar Cherbonneau, ouvrez-vous à moi, je suis
le médecin des âmes, vous êtes mon malade, et, comme le prêtre
catholique à son pénitent, je vous demande une confession
complète, et vous pourrez la faire sans vous mettre à genou.
—A quoi bon? En supposant que vous ayez deviné juste, vous
raconter mes douleurs ne les soulagerait pas. Je n’ai pas le chagrin
bavard,—aucun pouvoir humain, même le vôtre, ne saurait me
guérir.
—Peut-être,» fit le docteur en s’établissant plus carrément dans
son fauteuil, comme quelqu’un qui se dispose à écouter une
confidence d’une certaine longueur.
«Je ne veux pas, reprit Octave, que vous m’accusiez d’un
entêtement puéril, et vous laisser, par mon mutisme, un moyen de
vous laver les mains de mon trépas; mais, puisque vous y tenez, je
vais vous raconter mon histoire;—vous en avez deviné le fond, je ne
vous disputerai pas les détails. Ne vous attendez à rien de singulier
ou de romanesque. C’est une aventure très-simple, très-commune,
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