Quantification and the Quest for Medical Certainty

Quantification and the Quest

for Medical Certainty

Quantification and the Quest

for Medical Certainty

J. Rosser Matthews

PRINCETON UNIVERSITY PRESS

PRINCETON, NEW JERSEY

Copyright © 1995 by Princeton University Press

Published by Princeton University Press, 41 William Street,

Princeton, New Jersey 08540

In the United Kingdom: Princeton University Press, Chichester, West Sussex

All Rights Reserved

Library of Congress Cataloging-in-Publication Data

Matthews, J. Rosser, 1964–

Quantification and the quest for medical certainty /

J. Rosser Matthews.

p. cm.

Includes bibliographical references and index.

ISBN 0-691-03794-9

1. Clinical trials—History. 2. Medicine—Research—Statistical methods—History. I. Title

[DNLM: 1. History of Medicine, Modern. 2. Clinical trials—history. 3. Probability. WZ 55 M439g 1995]

R853.C55M38 1995

619'.09—dc20

DNLM/DLC

eISBN: 978-1-400-82180-8

R0

This book is dedicated to my mother and to the memory of my father

CONTENTS

Acknowledgments ix

INTRODUCTION 3

CHAPTER ONE

Probable Knowledge in the Parisian Scientific and Medical Communities during the French Revolution 8

CHAPTER TWO

Louis’s Numerical Method in Early-Nineteenth-Century Parisian Medicine: The Rhetoric of Quantification 14

CHAPTER THREE

Nineteenth-Century Critics of Gavarret’s Probabilistic Approach 39

CHAPTER FOUR

The Legacy of Louis and the Rise of Physiology: Contrasting Visions of Medical Objectivity 62

CHAPTER FIVE

The British Biometrical School and Bacteriology: The Creation of Major Greenwood as a Medical Statistician 86

CHAPTER SIX

The Birth of the Modern Clinical Trial: The Central Role of the Medical Research Council 115

CHAPTER SEVEN

A. Bradford Hill and the Rise of the Clinical Trial 131

CONCLUSION 141

Notes 151

Bibliography 177

Index 191

ACKNOWLEDGMENTS

AS IS OFTEN THE CASE with one’s first academic book, this manuscript had its origin as a doctoral dissertation which, in this case, was completed at Duke University and awarded through the history department. As such, my most immediate scholarly and intellectual debts are to members of my doctoral committee for training me. For his knowledge of the history of science as well as for his critical and editorial comments on innumerable drafts (both as a dissertation and in the subsequent revision to a book), I acknowledge my doctoral supervisor Seymour H. Mauskopf. In addition, I would like to express my appreciation to the historians of medicine Michael R. McVaugh and Peter C. English for their comments on this study at various points in its evolution. I would also like to thank Allan M. Brandt for agreeing to be on my final doctoral defense committee and raising important issues that I hope I have been able to incorporate in this revised manuscript.

Various other teachers over the years have provided intellectual stimulation that, no doubt, had an impact on the views I express in this book. Among those I would like to single out specifically in this regard are Lloyd S. Kramer and Orest Pelech for their courses in graduate school which introduced me to some of the broader issues involved in attempting to understand (and write about) the history of modern thought.

The intellectual inspiration for this study derives from the books, articles, and dissertations that have appeared in recent years on the history of probability and statistics by such contributors as Ian Hacking, Lorraine J. Daston, Stephen Stigler, Donald MacKenzie, Andrea A. Rusnock, Ulrich Tröhler, Harry M. Marks, the contributors to the two-volume work The Probabilistic Revolution, and Theodore M. Porter. I would like to thank Theodore M. Porter specifically for his comments, which helped transform this manuscript into a book.

Several libraries and archives have provided indispensable help in my research on this book. Among the library staffs that have been the most helpful are the interlibrary loan office of Perkins Library at Duke; Barbara Busse and Gayle M. Elmore of the Trent Collection in the history of medicine in the Duke University Medical Center Library; the National Library of Medicine, Bethesda, Maryland; and the Library of the College of Physicians, Philadelphia, Pennsylvania. I would like to acknowledge the following archives for permission to quote from papers housed in their collections: the American Philosophical Society—Raymond Pearl papers; the library of the London School of Hygiene and Tropical Medicine—Ronald Ross papers; and the Library, University College London—Francis Galton and Karl Pearson papers. In addition, I would like to acknowledge Major Greenwood’s grandsons Roger M. Greenwood and John M. Greenwood for their permission to quote from their grandfather’s correspondence in these various archives. I have made a good faith effort to locate the literary heirs of the other individuals whom I cite; however, so far I have been unable to locate any of them.

Several of my friends from graduate school have provided the intellectual, social, and emotional support that is indispensable in the production of scholarly research. Among the individuals who must be singled out are George Ehrhardt, Nancy Zingrone, and Carlos Alvarado.

Finally, I dedicate this book to my mother, Barbara M. Matthews, and to the memory of my father, John R. Matthews, Jr. (1920–1992). It is hard to express my degree of appreciation to them except to say that, if I have succeeded academically, the reason is that there were two people in the world who have always believed in me.

Any errors that remain are, of course, my own fault.

Quantification and the Quest

for Medical Certainty

INTRODUCTION

ONE OF THE MOST OBVIOUS contemporary examples of the effects of statistically based science both on public and on private life is the clinical trial. Since World War II, the trial has evolved into a standard procedure in the introduction of new drugs in most of the major Western industrial democracies. Its features include the use of a so-called control group of patients that do not receive the experimental treatment, the random allocation of patients to the experimental or control group, and the use of blind or masked assessment so that the researchers do not know which patients are in either group at the time the study is conducted. Enshrined in public policy since the 1970s,¹ the clinical trial nicely illustrates the desire of modern democratic society to justify its medical choices on the basis of the objectivity inherent in statistical and quantitative data.²

Even though the clinical trial has moved to the forefront of medical research only within the past generation, the use of comparative statistics in a therapeutic context has a much longer history, which this book will illuminate. My primary focus is three debates over the use of comparative statistics in a medical context, namely the dispute between the clinicians Risueño d’Amador and P.-C.-A. Louis before the Paris Academy of Medicine in 1837, the dispute between the mathematician Gustav Radicke and research physiologists conducted in the pages of the Archiv für physiologische Heilkunde during the 1850s, and finally the early-twentieth-century dispute between the British biometrician Major Greenwood and the bacteriologist Almroth Wright over the latter’s technique for diagnosing disease by measuring the opsonic index. My reasons for organizing this study around these three debates are multifaceted.

One obvious benefit of comparing debates that were carried on in different countries and in different time periods is the opportunity for both cross-national and cross-temporal comparison.³ Furthermore, the center of gravity of this study shifts to each country (France, Germany, Great Britain) at precisely the moment in time when that country was in a period of medical and/ or scientific ascendancy. I focus on debates among early-nineteenth-century Parisian clinicians as they were attempting to forge (in Michel Foucault’s words) the birth of the clinic.⁴ In like manner, I focus on debates among German physiological researchers when they were attempting to create the modern physiological research institute. Finally, I focus on a British context wherein Karl Pearson and his associates at University College London gave birth to what became, in effect, the first modern department of mathematical statistics. This study thus not only illuminates important debates over the use of a statistical methodology within a medical context; it also uses these debates to cast certain epochal transformations within the history of Western science and medicine into especially bold relief.

By analyzing how pioneering clinicians, physiologists, and bacteriologists viewed the novel method of statistical comparison, this study sheds new light on medical research and practice as a social and cultural activity⁵ and demonstrates that, despite the very real differences in outlook between the medical practitioner and the medical researcher, both share an antipathy toward methods of quantitative or statistical inference. For both the medical practitioner and the medical researcher, the amorphous concept of medical judgment (whether that judgment is executed at the bedside or the laboratory bench) cannot be reduced to a set of explicit rules. In short, medical judgment is a form of tacit knowledge.⁶

In addition to showing how these now-classic issues in the philosophy of science were debated in a historical context, the controversies over the use of statistical and probabilistic reasoning within medicine can also be embedded in a growing scholarly literature called the Probabilistic Revolution. This literature has dealt with such subjects as how the concept of chance became part of our conceptual vocabulary over the past two centuries and the relationship between probability and new standards of precision, argument, and objectivity.⁷ By showing how these concerns have been addressed in a specifically medical context, this study extends the analysis of a probabilistic revolution to a wholly new domain, namely the realm of medical therapeutic research.

The central concern of the first two chapters is the aforementioned debates before the Parisian Academies of Science and Medicine in the 1830s regarding what the Parisian clinician P.-C.-A. Louis (1787–1872) chose to call the numerical method, i.e., the attempt to determine therapy on the basis of statistical comparison. Louis maintained that the use of such a numerical method would confer scientific status on the clinical physician. His principal critic, Risueño d’Amador, maintained that medicine was an art rather than a science. The capstone of this debate came with the 1840 publication of Principes généraux de statistique médicale by Jules Gavarret, a former military engineer turned physician. Gavarret showed how to apply mathematical and probabilistic considerations to clinical statistics; however, his approach was rejected even by Louis’s supporters. They were more concerned with using numerical results to demonstrate empirical facts than to engage in probabilistic theorizing.

Even though Gavarret’s approach was never systematically put into practice during the course of the nineteenth century, his ideas were discussed by various nineteenth-century commentators, as Chapter Three demonstrates. Social statisticians (this study focuses largely on Anglo-French commentators) downplayed Gavarret’s mathematical concerns as introducing needless technical abstraction into otherwise clear statistical evidence. They were more concerned with demonstrating the essentially lawlike character of widespread social phenomena such as the spread of disease. Chapter Three concludes by focusing on how German clinicians and epidemiologists differed from Anglo-French contemporaries in their attitude toward Gavarret. Reflecting their strong institutional ties to the emerging research university, German commentators tried to modify Gavarret’s formulas so that medical therapy could become both scientific and practicable.

Chapter Four studies two related issues: the legacy of Louis’s numeral method and how physiologists defined their research agenda in opposition to Louis by claiming that experimentation on living organisms in the laboratory (rather than merely collecting statistics in the clinic as Louis had done) was the key to providing medicine with a scientific foundation. The clearest exponent of this view was the French experimental physiologist Claude Bernard (1813–1878). When the physiologists did make generalizations about their experimentally determined data, they relied on their professional medical expertise, what they called the logic of facts. This view of the physiologists that they were uniquely qualified to interpret physiological data is illustrated concretely at the end of the chapter through an analysis of the Radicke-Vierordt debate.

The shift from statistics as a broadly descriptive tool for social analysis to a method of mathematical and scientific inference was inaugurated by the pioneering work of Francis Galton (1822–1911) in establishing what Ian Hacking has called the autonomy of statistical law.⁸ This idea is central to the fifth chapter of this book. As a result of his researches into heredity, Galton pioneered the concept of correlation: the degree to which any two series of numbers were correlated would be represented as a percentage from 0 to 1. Galton found a willing disciple of the concept of correlation in Karl Pearson (1857–1936), a professor of applied mathematics at University College London. In the context of furthering the study of heredity, Pearson created what became, in effect, the first department of modern statistics conceived as an applied mathematical discipline. Among Pearson’s students was the physician Major Greenwood (1880–1949), who later furthered this mathematical and scientific vision of statistics in the milieu of medical research by holding posts successively at the Lister Institute for Preventive Medicine, the Medical Research Council, and the chair of Epidemiology and Vital Statistics at the newly created London School of Hygiene and Tropical Medicine.

In this part of the book, I have augmented the printed primary sources by studying the private correspondence of the principal players involved. The reasons for introducing archival evidence in the analysis of the third debate are numerous. In the two earlier debates over statistical methodology, the technical or mathematical issues had always been introduced by outsiders, or figures marginal to mainstream medical thought. In the highly stratified world of post-Napoleonic French higher education, Gavarret had the unique experience of having been trained both at the Ecole Polytechnique and as a physician. Similarly, Radicke was a mathematician and meteorologist by profession, not a physician. Thus, these debates were isolated events rather than the basis for a medical or statistical research program. In Greenwood’s career, however, one sees the first attempt to create the mathematically trained medical statistician as a new professional role within the world of medical research. Also, Greenwood attempted to tie mathematical statistical methods to the domain of laboratory-based research rather than the predominantly social concerns of earlier generations.

The sixth chapter continues to focus on the attempts by Greenwood and his American counterpart Raymond Pearl (1879–1940) to create the new scientific professional role for the statistician in the medical research establishment. Among the various strategies they deployed were writing textbooks, publishing in scientific journals, training students, and, in the case of Greenwood, writing historical narratives on the role of statistics in medicine. One of Greenwood’s students who would eventually succeed him both at the Medical Research Council and the London School of Hygiene and Tropical Medicine was Austin Bradford Hill (1897–1991). In 1946 Hill designed for the Medical Research Council what is generally recognized as one of the first modern clinical trials to determine the effect of streptomycin on tuberculosis. In the trial Hill used the principle of randomization in assigning patients to the experimental or control groups, thereby displaying an incorporation of elements of chance into a scientific experiment.

Chapter Seven focuses on the efforts of Hill and his associates during the 1950s and early 1960s to convince the medical profession at large of the enormous utility of introducing the double-blind clinical trial as a standard procedure for determining the efficacy of new drugs. During this period Hill and his followers published textbooks and anthologies, attempted to offer instruction in statistical methods, and planned scholarly conferences on the role of statistical methods within medicine. These proselytizing efforts for a statistical methodology were of undeniable importance in laying the groundwork for the triumph of the clinical trial; however, the catalyst that eventually brought the clinical trial to the forefront of public and medical debate was the Thalidomide scare of the early 1960s. This scare led to the institutionalization of the clinical trial as the ultimate arbiter in determining the efficacy of experimental drugs in most of the Western industrial democracies. Thus, I argue that the clinical trial eventually triumphed less because of internal debate within the medical profession and more because society at large decided that, in an era of highly potent industrially produced drugs, the decisions of the medical profession would have to be regulated.

In the Conclusion I speculate on how this historical study can provide a framework for understanding contemporary debates about the clinical trial, both political and academic. Politically, the design and implementation of the clinical trial offers a unique opportunity for engaging some of the most hotly contested issues of our day: race, class, gender, the AIDS epidemic, and even abortion. Academically, the objectivist rhetoric of the supporters of the clinical trial makes it an ideal topic for those engaged in the ongoing multidisciplinary attempt to rethink objectivity.⁹

Chapter One

PROBABLE KNOWLEDGE IN THE PARISIAN SCIENTIFIC AND MEDICAL COMMUNITIES DURING THE FRENCH REVOLUTION

IN THE TWILIGHT of the Enlightenment, the last years of the Old Regime in France, Louis XVI appointed A.R.J. Turgot (1727–1781) to the post of Controller-General in 1774 to help deal with the impending financial crisis. Turgot was a friend of the philosophes. He was committed not only to solving particular social and financial problems but also to realizing the possibility of a science of man based on reason and experience rather than tradition. His appointment proved decisive in forging strong links between the leading scientific thinkers of the day and the government that desired to use their expert knowledge—what Charles Gillispie has characterized as a union of science and polity.¹

One of the first problems that Turgot took on was public health. To deal with a cattle plague that emerged in November of 1774, he established a commission on epidemics headed by Felix Vicq d‘Azyr (1748–1794), the personal physician to Marie Antoinette and a member of both the Académie Royale des Sciences and the Académie Française. Within two years, this commission evolved into the Royal Society of Medicine, with Vicq d’Azyr as permanent secretary. This new society helped pioneer the collection of statistical data on matters of epidemics, epizootics, and meteorology. Although it was abolished during the French Revolution in 1793, it became the model for successor institutions such as the Royal Academy of Medicine in the nineteenth century.²

In addition to using his position in the government to advance the cause of public health, Turgot was also interested in questions of constitutional reform. He envisaged reordering the French state on a representative basis. Village assemblies would elect district assemblies; district assemblies would elect provincial assemblies; and provincial assemblies would then elect a national assembly. One of the principal legacies of Turgot’s vision was the inspiration of the Marquis de Condorcet (1743–1794), a mathematician and Secretary of the Parisian Academy of Sciences, to apply his mathematical training to the problem of the reform of elected assemblies. In his 1785 work Essai sur l’application de l’analyse à la probabilité des décisions rendues à la pluralité des voix, Condorcet applied the mathematical theory known as the calculus of probabilities to voting patterns of judicial tribunals. He attempted to determine the probability that the judgment rendered by a tribunal was correct.³

Although Condorcet was motivated to undertake his study by his particular association with Turgot, his belief that a relationship existed between the calculus of probabilities and legal or constitutional issues can be seen as a function of broader concerns within eighteenth-century probabilistic thinking. As Lorraine Daston has cogently argued, the calculus of probabilities was less a theory than a domain of applications throughout the eighteenth century. These applications were often framed in terms of the legalistic notions of equity and expectation as formulated in fair contracts. Daston sees these legal notions as central to the emergence of probability theory because there had existed in continental legal thought a system of so-called legal proofs that associated circumstantial evidence with certain numerical fractions in order to determine the likelihood that the charged individual was guilty.⁴

The principal intellectual inspiration for Condorcet’s association of probability with legalistic concerns was the posthumously published 1713 work of Jakob Bernoulli, the Ars Conjectandi. In addition to spelling out various methodological rules for determining whether an individual was guilty or not, Bernoulli’s work was significant because it developed a theory of inverse probability. This theory declared that the frequency of an event would begin to approach its probability of occurrence provided the number of observations was sufficiently large. On the basis of Bernoulli’s work, Condorcet saw the possibility of extending the calculus of probabilities beyond games of chance to practically all areas of human judgment. He declared that Bernoulli seemed to recognize more clearly than anyone the full potential of the applications of this calculus, and the manner in which it could be extended to almost all questions subject to reasoning.⁵ Condorcet saw both the physical and social sciences as related in a kind of graduated skepticism. In his acceptance speech before the Academy of Sciences in 1782, Condorcet had declared: In meditating on the nature of the moral sciences, one cannot indeed help seeing that, based like the physical sciences upon the observation of facts, they must follow the same methods, acquire an equally exact and precise language, attain the same degree of certainty.⁶

Condorcet’s specific conclusions about how to apply probability theory were less important than the role he played in directing his younger and more mathematically proficient colleague Pierre-Simon Laplace (1749–1827) to take up probability theory. Laplace had come to Paris in the 1760s as a young man and soon received the patronage of the mathematician and philosophe Jean Lerond d’Alembert (1717–1783) on the basis of his mathematical aptitude. Beginning in the 1770s, Laplace published a series of papers on various aspects of mathematical probability ranging over both theoretical mathematical issues and practical applications such as demography and vital statistics. In his popular work Essai philosophique sur les probabilités (1814), a collection of ten popular lectures originally given at the Ecole Normale in 1795, Laplace argued for the wide domain of possible applications for the calculus of probabilities:

Strictly speaking it may even be said that nearly all our knowledge is problematical; and in the small number of things which we are able to know with certainty, even in the mathematical sciences themselves, the principal means for ascertaining truth—induction and analogy—are based on probabilities; so that the entire system of human knowledge is connected with the theory set forth in this essay.⁷

Laplace’s belief that probability theory could be used to overcome the insufficiencies of the human intellect in potentially all domains of analysis has been attributed by Daston to his acceptance of the psychological views of Etienne Condillac. According to Condillac’s empiricist epistemology, all ideas are derived from sense experience. Thus, in a well-ordered mind, judgment would have a kind of mathematical precision that the theory of probability could capture; subjective belief would be given mathematical and objective order.⁸ As Laplace put it, probability theory was only common sense reduced to a calculus.⁹

Laplace explicitly cited medical therapy as a possible domain for applying the calculus of probabilities. He advised physicians that the preferred method of treatment "will manifest