Profiles in Medical Courage: Causation and Austin Bradford Hill

“The secret language of statistics, so appealing in a fact-minded culture, is employed to sensationalize, inflate, confuse, and oversimplify”

-Darrel Huff in How to Lie with Statistics

Abstract

Austin Bradford Hill was a British epidemiologist and statistician who is best remembered for two landmark pulmonary studies. He was the statistician on the Medical Research Council Streptomycin in Tuberculosis Trial. This is regarded as the first randomized clinical trial. The second was the demonstration of the connection between cigarette smoking and lung cancer. However, Hill’s most lasting contribution may be his establishment of a group of conditions necessary to provide adequate evidence of a causal relationship between an incidence and a consequence, widely known as the Bradford Hill Criteria of Causation. In this profile of medical courage we examine his remarkable background that led to the epidemiological equivalent of Koch’s postulates.

Introduction

Recently, two articles have appeared in the Southwest Journal of Pulmonary and Critical Care which involved Sir Austin (Tony) Bradford Hill. The first was Dr. Raschke’s review of Doll and Bradford Hill’s landmark study on the etiology of lung cancer (1). The second was the prior profile in medical courage article on Archie Cochrane, Bradford Hill’s student (2). These prompted me to conduct a study of Bradford Hill and his remarkable career. Although both of his studies are important, his criteria for causation may be his greatest legacy (3). In a time when the unscrupulous utter half-truths to associate an incident with a consequence, Bradford Hill’s criteria for causation are as relevant today as they were when first published in 1965 (3).

Early Life

Austin Bradford Hill was born into an eminent British family in 1897. His great-great uncle, Sir Rowland Hill, invented the rotary press and introduced the first mail stamp 1840.  His father, Sir Leonard Hill, was professor of physiology at the University of London and did seminal work on the cerebral circulation and decompression sickness of divers.

From childhood, Tony, as he came to be called, wanted to be a doctor but the First World War intervened.  He volunteered as an aviator for the Royal Navy and was sent to the Greek islands to support the attack on the Dardanelles.  His plans were cut short when in November 1917 he was diagnosed with severe pulmonary tuberculosis and was sent home to die. The progress of the disease changed after a therapeutic pneumothorax and he slowly improved. While recovering he contemplated his career. Medicine seemed to be out of the question and he opted to study economics by correspondence courses from the University of London as he convalesced.  Three years later he obtained a Bachelor of Science degree– having attended the university only twice to take examinations.

Early Career

Tony had no desire to make a career in economics. His father’s friend, the prominent epidemiologist, Major Greenwood, helped him obtain a grant from the Medical Research Council (MRC) to investigate the reason for the high mortality of young adults in rural Essex. His investigations concluded that the excess was most likely due to selective migration of the fittest to work in urban areas. The success of his research enabled him to obtain further appointments with the MRC and extend his knowledge of statistics by attending courses at the University of London led by Karl Pearson. In 1927 he followed Major Greenwood to the newly-formed London School of Hygiene and Tropical Medicine and taught statistics to at the Postgraduate Medical School at Hammersmith in London (Figure 1).

Figure 1. Austin Bradford Hill lecturing.

His lectures were published as a series of 17 popular articles in the Lancet during 1937 and later in book form, Principles of Medical Statistics (4). The book became very popular and went through multiple editions making him the best known medical statistician in the world, which is remarkable for someone who held no degree in medicine or statistics. In this book he discussed epidemiological methods for investigating the causes of non-infectious diseases, and introduced randomization. He emphasized the need to compare like with like, to avoid potential sources of bias and to allow for the play of chance. However, he avoided the use of mathematical formulas and set out procedures that needed to be adopted in plain English. By so doing he secured the attention of a medical profession that largely had no basic knowledge of mathematics or statistics. The book was important in persuading physicians to present their research results both logically and quantitatively.

He wrote of his lectures, "I deliberately left out the words ‘randomisation’ and ‘random sampling numbers’ at that time, because I was trying to persuade doctors to come into controlled trials in the very simplest form and I might have scared them off. I think the concepts of ‘randomisation’ and ‘random sampling numbers’ are slightly odd to the layman, or for that matter, to the lay doctor, when it comes to statistics. I thought it would be better to get the doctors to walk first, before I tried to get them to run. So I had been thinking about controlled trials for all of those 10 years and hoping for an opportunity that might arise” (5).

Landmark Investigations

After the War, Bradford Hill succeeded Greenwood as Professor of Medical Statistics and directed the Statistical Research Unit of the Medical Research Council (MRC). He was particularly influenced by one of Pearson’s students, Ronald Aylmer Fisher, who had pioneered the use of randomization in agricultural experiments. Up until this time medical investigations were usually a before-and-after design, i.e., patients were treated and the results compared to historical controls. He realized that confounding variables so inherent in before-and-after studies could change results. Although Bradford Hill had advocated randomization in his book, he had not been specific about the methods.

In 1946 Bradford Hill was presented with the opportunity to put his theories into practice. He persuaded the MRC to launch randomized controlled trials, one in preventive medicine to test a pertussis (whooping cough) vaccine, the other in clinical medicine to assess the effect of streptomycin in the treatment of pulmonary tuberculosis (6). The latter is generally regarded as the first randomized medical trial with patients randomized to a treatment group and a control group by a process using random sampling numbers and sealed envelopes.  These trials were followed by a remarkable stream of articles on the principles of clinical trials including practical and ethical problems.

Meanwhile he launched, with Richard Doll, a case-control study comparing lung cancer patients with matched controls. This study showed conclusively that smoking was the predominant risk factor in developing lung cancer (7). This was followed by other case-control studies, and a long-term prospective study of smoking and health which demonstrated that lung cancer was not the only disease to be caused by smoking. This cohort study was conducted on British doctors, an ideal population whose cooperation was testimony to the respect with which Bradford Hill's work was regarded by his medical colleagues. He was by nature a cautious man, and he had been careful initially to claim that a causal effect of smoking on lung cancer was only one of a number of possible explanations for the association. As the evidence mounted he accepted the causal link as being overwhelmingly the most likely explanation. The reception was lukewarm and in particular he was disturbed by skeptical remarks from Ronald Fisher.  Interestingly, it was Fisher who had nominated Hill as a Fellow of the Royal Society in 1954.

In response to criticism, he formulated 9 principles of causation which were published in 1965 and are listed below (3). Although originally presented as a way of determining the causal link between cigarette smoking and lung cancer, Bradford Hill's Criteria forms the basis of modern epidemiological research. Furthermore these principles are equally applicable to other sciences which study causal relationships between phenomena. 

Bradford Hill’s Criteria for Causation

1. Strength. This is defined by the size of the association as measured by appropriate statistical tests. The stronger the association, the more likely it is that the relation of "A" to "B" is causal. For example, lung cancer death rates are 10-30 times higher in smokers than in nonsmokers.
2. Consistency. The association is consistent when results are replicated in studies in different settings using different methods. As an example, Bradford Hill points out that an association between lung cancer and smoking was found in 29 retrospective and 7 prospective studies in 1964.
3. Specificity. This is established when a single putative cause produces a specific effect. This is considered by some to be the weakest of all the criteria. Lung cancer attributed to cigarette smoking does not meet this criterion because the death rate of smokers is higher from other causes in addition to lung cancer. When specificity of an association is found, it provides additional support for a causal relationship. However, absence of specificity in no way negates a causal relationship.
4. Temporality. Exposure always precedes the outcome. If a factor is believed to cause a disease, then the factor must precede the occurrence of the disease. This is the only absolute criterion. In the case of lung cancer, cigarette smoking invariably occurs before the development of the cancer.
5. Biological gradient. By this Bradford Hill means a dose-response relationship. The death rate from lung cancer increases as the number of daily cigarettes smoked increases.
6. Plausibility. The association agrees with currently accepted understanding of pathological processes. In 1965, it was known that tobacco tar induced cancer when painted on the skin of mice (8).
7. Coherence. The association should be compatible with existing knowledge. Both the incidence of lung cancer and cigarette smoking rose beginning after World War I. In 1964 both the incidence of lung cancer and cigarette smoking were lower in women than in men.
8. Experiment. The condition can be prevented or ameliorated by an appropriate experimental regimen. The incidence of lung cancer can be lowered by quitting smoking.
9. Analogy. In judging whether a reported association is causal, it is necessary to determine the extent to which researchers have taken other possible explanations into account and have effectively ruled out such alternate explanations. For example, in their investigations Doll and Bradford Hill were careful to match lung cancer patients with controls to eliminate any potential bias related to exposure to occupational or environmental toxins. A questionnaire was designed to identify potential confounding variables including whether cigarette holders and petrol lighters were used, occupation, residence near a gasworks, exposure to different types of home heating, and previous respiratory illnesses and shown to be independently unrelated to lung cancer.

Bradford Hill pointed out that no formal tests of significance could answer the above questions. During his career, he used the simplest mathematical techniques. It is remarkable that as a statistician he relied so little on statistics and he often pointed out that he had no formal training in medicine or statistics. His success was due to a combination of factors but probably most importantly communication of honest experimental and statistical concepts in a way that nearly all could understand.

Hill died in 1991 a few months short of his 94^th birthday. Up until the time of his death he continued to collect a 100%, war-related, disability pension from the British Government. In hindsight, his development of tuberculosis may have been a fortuitous occurrence for medical investigation. Despite his disability, he did rather well and should be remembered for his courage in standing up for honest, unbiased research.

Richard A. Robbins, MD

References

1. Raschke RA. May 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:178-9.
2. Robbins RA. Profiles in medical courage: evidence-based medicine and Archie Cochrane. Southwest J Pulm Crit Care 2012;5:?-?.
3. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58:295-300.
4. Hill AB. Principles of Medical Statistics. London: Lancet, 1937.
5. Hill AB. Suspended judgement, memories of the British streptomycin trial, the first randomised clinical trial. Control Clin Trials 1990;1:77-79.
6. Medical Research Council. Streptomycin treatment of pulmonary tuberculosis: a report of the Streptomycin in Tuberculosis Trials Committee. British Medical Journal 1948;2:769-82.
7. Doll R and Hill AB.  A study of the aetiology of carcinoma of the lung.  Br Med J 1952;2:1271-86.
8. Croninger AB, Graham EA, Wynder EL. Experimental production of carcinoma with tobacco products. V. Carcinoma induction in mice with cigar, pipe, and all-tobacco cigarette tar. Cancer Res 1958;18:1263-71.

Reference as: Robbins RA. Profiles in medical courage: causation and Austin Bradford Hill. Southwest J Pulm Crit Care 2012;5:115-20. (Click here for PDF version)

Profiles in Medical Courage: Evidence-Based Medicine and Archie Cochrane

“Medicine is a science of uncertainty and an art of probability.”

-Sir William Osler

Abstract

Archibald (Archie) Cochrane is often credited with being the inspiration for evidence-based medicine. His influential 1971 book, “Effectiveness and Efficiency”, strongly criticized the lack of reliable evidence behind many common healthcare practices. His call for a collection of systematic reviews led to the creation of The Cochrane Collaboration, named in honor of him. Archie Cochrane's life was a tortuous one, which included psychoanalysis, service in two wars, and studies of pneumoconiosis, tuberculosis and healthcare delivery. In this profile of medical courage we explore not only his thoughts on healthcare but his extraordinary background that shaped his ideas.

Early Life

Archie Cochrane was born in 1909 in Galashiels, Scotland, a cloth manufacturing town 30 miles south of Edinburgh. His family was wealthy mill owners that instilled in Archie the principles of self-reliance and accomplishment. This was important since his father died in the First World War when Archie was 8. However, Archie was financially secure since as the first born, he inherited a private income.

By all accounts, he was a bright student. After attending preparatory school at Rhos-on-Sea in Wales, Archie won a scholarship to Uppingham School in Rutland, England, where he became a school prefect and a member of the rugby team. In 1927, he won a scholarship to King’s College Cambridge, where he graduated in 1930 with honors in natural sciences. His inheritance enabled him to continue studying, and during 1931 he worked on tissue culture at the Strangeways Laboratory at Cambridge and later in Toronto. However, he soon tired of what he concluded was trivial research and abandoned basic studies.

Psychoanalysis

At about this time he became anxious about his sexual development. He had developed anejaculation, a condition where he was unable to ejaculate.  This led him to seek medical help but he received little sympathy from the British doctors. However, he found the doctors at the Kaiser Wilhelm Institute in Berlin were willing to take his problem seriously. Between 1931 and 1934 he underwent psychoanalysis with Freud’s leading lay analyst, Theodor Reik. The psychoanalysis began initially in Berlin, but like Freud, Reik was a Jew. Archie followed Reik first to Vienna and later The Hague as Reik fled from Hitler. Archie did some medical studies in Vienna and Leiden during this time, and published his first paper (Elie Metchinikoff and his theory of an ‘instinct de la mort’). Unfortunately, the psychoanalysis did not cure his condition which plagued him for the rest of his life. However, his sojourn in Europe instilled in him a hatred of fascism and a skeptical attitude not only of psychoanalysis, but or all theories which had not been validated by testing. Later in his life, Cochrane condemned the entire field of psychiatry for “using a large number of therapies whose effectiveness has not been proven” and for being “basically inefficient” (1).

Spanish Civil War

Disenchanted, he returned to London in 1934 and continued his studies as a clinical medical student at University College Hospital. His experiences in Europe, his hatred of fascism, and his sense of social justice led him to joint the Socialist Medical Association. In 1936, this group of doctors, medical students and nurses met in London to consider ways of sending medical help to Republicans fighting fascism in the Spanish Civil War. This was viewed by Archie as important since the addition of Spain as a fascist ally to Germany and Italy would likely result in the fall of France and England to fascist aggression. The Socialists decided to send doctors, nurses and medical students to Spain to assist the Republicans and Archie abandoned his studies in order to serve as a volunteer.

Figure 1. Panel A. Archie Cochrane as a medical student. Panel B. As a volunteer in the Spanish Civil War with a “flourishing red beard” (From Cardiff University Library, Cochrane Archive, University Hospital Llandough). 

He served at Grañén near Huesca on the Aragon front and the siege of Madrid. Although not qualified as a physician, he served in an ambulance unit as well as performing duties such as triage in the hospital. During this time Archie had contact with the Communists that made up much of the Republican army. Like many intellectuals of that period, Archie had been attracted by Marx during his undergraduate studies. However, his experience in Spain turned him against communism, but he remained a man of the left throughout his life. After about a year all British medical students were ordered to return home to qualify. Archie had grown sick of the war and was happy to comply.

World War II

He resumed his clinical studies at University College Hospital in 1937, and qualified in 1938. Until the outbreak of the Second World War he worked first as a house physician at the West London Hospital and then as a research assistant University College Hospital. At the beginning of World War II, he enlisted in the Royal Army Medical Corps and served first in Egypt and then as a medical officer in “D” Battalion Layforce, a commando unit. The one military action in which he was involved ended disastrously in Crete when the British troops surrendered and Archie was taken as a prisoner of war (POW).

Figure 2. Archie Cochrane as a POW with his identity card (From Cardiff University Library, Cochrane Archive, University Hospital Llandough).

Shortly after his capture in June 1941, he was sent to a POW camp at Slonica in Greece where he conducted his “first, worst and most successful clinical trial” (2). The camp was a run-down, overcrowded army barracks, infested with bed bugs. The diet was minimal-breakfast: unsweetened "ersatz" coffee; midday: a bowl of vegetable soup; evening: two slices of plain bread- in all, about 400 to 500 calories. Archie was appointed chief medical officer by the Germans, not because of his medical abilities, but because of his time in Germany he spoke fluent German. He also became the senior British officer in charge of 8000 demoralized, hungry British prisoners of war.

In August an epidemic of jaundice accompanied by edema began and rapidly progressed. The German doctors claimed that the edema was due to the sun and not to starvation. Archie was also afflicted with severe jaundice and pitting edema above the knees. He decided that something must be done, and that he was the only one who could do it. He hypothesized, incorrectly as it turns out, that the prisoners were suffering from “wet beriberi" due to a vitamin deficiency. Archie bought some yeast on the black market and recruited 20 young prisoners and divided them between two wards. Each man in one ward received two spoonfuls of yeast daily. Those in the other ward received one tablet of vitamin C. By the fourth day there was a conclusive difference in the edema. Archie asked the members of each ward whether they felt better, the same, or worse. Nine out of ten in the "yeast" ward felt better; none in the other.

Archie showed the results to the Germans and asked for yeast and more food. They said, as usual, that they would see what they could do. However, a young German doctor pointed out that the results were incontrovertible and they could be prosecuted for war crimes unless that did something. This led to the unexpected, the Germans actually produced the yeast and the epidemic was quashed. On reflection, Archie realized the edema was not wet beriberi. Furthermore, his trial numbers were too small, the time too short, and the outcome measurements poor. Yet the treatment worked. Archie later speculated that the small amount of protein in the yeast raised the plasma proteins sufficiently to correct fluid imbalance that led to the edema (2).

Archie’s second experience in POW life at Elsterhorst, Germany was very different. He was assigned to the medical section where there were two other British doctors, who had been captured at Dunkirk. All the POWs with tuberculosis (most of whom were far advanced) of all nationalities, were herded together behind the wire. Archie knew a certain amount about tuberculosis and offered to take over that section of the medical work. Conditions were in many ways not too bad. Through Red Cross parcels there was sufficient food. Archie was able to 'screen' patients and do sputum 'smears' but radiographs were very limited. He could give patients bed rest, pneumothorax, and pneumoperitoneum. There was a French physiologist, an expert in 'adhesion-section', and thoracoplasty was a possibility. This tuberculosis work took up only a small part of Archie’s time. He realized that the rest of efforts must be devoted to "care" as the chance of a cure among these cases was minimal.

He would later state that “I remember at that time reading one of those propaganda pamphlets, considered suitable for POW medical officers about ‘clinical freedom and democracy’. I found it impossible to understand. I had considerable freedom of choice of therapy: my trouble was that I did not know which to use and when. I would gladly have sacrificed my freedom for a little knowledge. I had never heard of ‘randomized controlled trials’, but I knew that there was no real evidence that anything we had to offer had any effect on tuberculosis, and I was afraid that I shortened the lives of some of my friends by unnecessary intervention” (1).

Post-War Studies

After the War, Archie continued his studies. He studied preventive medicine at the London School of Hygiene and Tropical Medicine. There he was greatly influenced by Austin Bradford Hill’s teaching on randomized clinical trials and acknowledged Bradford Hill’s influence for the rest of his life. In 1947, Archie won a Rockefeller Scholarship and went to the Henry Phipps Clinic in Philadelphia, where he became interested in x-ray studies of pulmonary tuberculosis and developed what became a lifelong interest in observer error.

Academic Career

After returning from Philadelphia in 1948, Archie began his academic career at the recently formed Medical Research Council’s Pneumoconiosis Research Unit in Penarth, near Cardiff in South Wales. He initially conducted groundbreaking comparative studies of dust levels in the coal mines of South Wales. Two years later, he launched the Rhondda Fach study to investigate the etiology of progressive massive fibrosis and worked at the Pneumoconiosis Research Unit for over a decade. His main interests were the x-ray classification of coal workers’ pneumoconiosis and the relationship between x-ray categories, dust exposure, and disability. His interest in this field continued for the rest of his life, as reflected in the completion during 1974 to 1986 of twenty year and thirty year follow-up studies of the population of the Rhondda Fach (3-6).

Figure 3. Archie Cochrane in 1949 (From Cardiff University Library, Cochrane Archive, University Hospital Llandough).

Archie’s research achieved very high response rates in surveys and follow-up studies probably due to the team of disabled miners he formed to help maximize survey follow-up rates. This approach was new and revolutionary at the time. The quality of Archie’s research was reflected in the decision by the Medical Research Council to invite him to establish and direct a new epidemiology unit based in Cardiff in 1960. Archie was appointed to the David Davies Chair of Tuberculosis and Diseases of the Chest at the Welsh National School of Medicine. Under Archie’s direction, the Epidemiology Unit quickly established an international reputation for the quality of its surveys and studies of the natural history and etiology of a wide range of common diseases, including anemia, glaucoma, asthma, and gallbladder disease.

Archie is probably best remembered for his advocacy of randomized controlled trials. He always acknowledged influence of Bradford Hill in introducing him to the principles of using these studies to obtain unbiased estimates of the effects of healthcare interventions. He coordinated a wide variety of randomized trials to evaluate pharmaceutical, surgical and health service interventions. The trials with the most enduring and important implications for human health were those done in collaboration with Peter Elwood and included the first studies showing that aspirin could reduce the incidence of cardiovascular diseases (7)

His interest in health care delivery extended to a trial to determine where patients with an uncomplicated myocardial infarction should recover-either at home or in the hospital (8). After several unsuccessful attempts and over the protests of the cardiologists, Archie finally succeeded in receiving approval to start the trial. An interim analysis was planned and Archie gathered the hospital staff to present the results. He passed out a table and began by pointing out that none of the results were statistically significant. Archie went on to say, “Well gentlemen, it turns out that you were right and I was wrong. It is dangerous for patients to be cared for at home and they should be in the hospital.” An immediate cry from the cardiologists went up that “You’re killing people with your clinical trial” and they demanded that Archie stop the study. Archie let the commotion die and replied, “Well that’s very interesting, gentlemen, because when I gave you the table of results, I swapped the columns around. It turns out that your hospitals are killing people and they should be at home. Would you like to close down the trial now; or should we wait until the best results?” Archie referred to the cardiologists’ attitude as the “God complex” (8). By this he meant, no matter how complex the problem, the person has an overwhelming belief that they are infallibly right in their solution.

An invitation from the Nuffield Provincial Hospitals Trusts to prepare the 1971 Rock Carling Lecture provided Archie with an opportunity to speak on controlled clinical trials.  The book that resulted from the lecture, “Effectiveness and efficiency: random reflections on health services” (1), promptly became influential. He emphasized three themes in the book: 1. the importance of using randomized trials to identify which health service interventions are effective; 2. the relevance of assessing the costs or efficiency of the options available; and 3. the importance of equitable access to effective treatments.

Recognition and Later Years

In the year the book was published, 1972, Archie became the first president of the new Faculty of Community Medicine of the Royal College of Physicians (subsequently Faculty of Public Health). He received an honorary doctorate from the University of York the following year; was Dunham Lecturer at Harvard in 1974; became an honorary fellow of the American Epidemiological Association in 1975; and, in 1977, he received an honorary doctorate from Rochester University and became an honorary fellow of the International Epidemiological Association.

Figure 4. Archie Cochrane after retirement (From Cardiff University Library, Cochrane Archive, University Hospital Llandough).

Now with time to reflect, Archie followed up his criticism of the medical profession  in 1979 by stating, “It is surely a great criticism of our profession that we have not organized a critical summary, by specialty or subspecialty, adapted periodically, of all relevant randomized controlled trials” (9). In particular he challenged the obstetric profession for not having used the randomized controlled trial design to ascertain whether interventions related to pregnancy and childbirth were effective. He awarded the “wooden spoon” to obstetrics but the “silver spoon” to phtisiology (the study of tuberculosis) because of his mentor’s, Sir Austin Bradford Hill’s, landmark trials on the use of streptomycin (9). A few years after his death, Archie’s challenge led Iain Chalmers, an obstetrician, and his co-workers to create the Oxford Database of Perinatal Trials (10). Based on this database of controlled clinical trials, it was quickly realized that, to keep up with the rapid developments in the fields of perinatology and neonatology, the published reviews required timely updates. This realization formed the basis for the Cochrane Collaboration, which was established in the early 1990s, and had the aim of helping make well-informed decisions about health care (11). Thousands of volunteers are now involved in preparing and maintaining systematic reviews of randomized trials and other evidence within this international, non-profit organization. Cochrane Reviews are published electronically in The Cochrane Database of Systematic Reviews, the principal element of The Cochrane Library.

Legacy

Archie Cochrane died of cancer in 1988 after a long illness. His life has been described in an autobiography written with the assistance of Max Blythe (12). He did not found the Cochrane Collaboration as commonly believed, although he undoubtedly would be honored to have it named after him. Archie would be delighted with the Collaboration’s 10 principles: 1. collaboration; 2. building on the enthusiasm of individuals; 3. avoiding duplication; 4. minimizing bias; 5. keeping up to date; 6. striving for relevance; 7. promoting access; 8. ensuring quality; 9. continuity; and 10. enabling wide participation. Undoubtedly, if he were alive today, he would have awarded the Collaboration his silver spoon.

Some have questioned whether the Cochrane Collaboration and evidence-based medicine are a threat to physician autonomy. The Lancet has decried evidence-based medicine as an internal threat to the autonomy of the physician (13). Similar fears were expressed by Feinstein and Horwitz (14) in their critique of evidence-based medicine, calling it, “A new form of dogmatic authoritarianism may . . . be revived in modern medicine, but the pronouncements will come from Cochranian Oxford rather than Galenic Rome” (14). However, Hill (15) dismisses these fears and adds the comment that physician autonomy would have been the last of Cochrane’s concerns. I disagree.  Archie would have been very concerned. He would have recognized those with the God complex who cite studies that lack scientific rigor as evidence based medicine. Furthermore, he would have abhorred that this is used by some to advance their own biases or conflicts of interest.  Archie would undoubtedly have viewed these authoritarian and intolerant views of medical practice as disturbing as the lack of evidence and awarded them the wooden spoon.

Richard A. Robbins, MD

Editor, Southwest Journal of Pulmonary and

   Critical Care Medicine

References

1. Cochrane AL. Effectiveness and efficiency: random reflections on health services. London: Nuffield Provincial Hospitals Trust; 1973.
2. Cochrane AL. Sickness in Salonica: my first, worst, and most successful clinical trial. BMJ 1982; 289;1726-7.
3. Cochrane AL, Haley TJ, Moore F, Hole D. The mortality of men in the Rhondda Fach, 1950-1970.Br J Ind Med 1979;36:15-22.
4. Cochrane AL, Moore F, Baker IA, Haley TJ. Mortality in two radom samples of women aged 55-64 followed up for 20 years. Br Med J 1980;280:1131-3.
5. Atuhaire LK, Campbell MJ, Cochrane AL, Jones M, Moore F. Mortality of men in the Rhondda Fach 1950-80. Br J Ind Med 1985;42:741-5.
6. Atuhaire LK, Campbell MJ, Cochrane AL, Jones M, Moore F. Specific causes of death in miners and ex-miners of the Rhondda Fach 1950-80. Br J Ind Med 1986;43:497-9.
7. Elwood PC, Cochrane AL, Burr ML, Sweetnam PM, Williams G, Welsby E, Hughes SJ, Renton R. A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J 1974;1(5905):436-40.
8. Harford T. Trial, error and the God complex. Available at: http://www.ted.com/talks/tim_harford.html (accessed 7/10/12).
9. Cochrane AL. Medicine For the Year 2000. London: Office of Health and Economics; 1979. 1931–1971: A critical review with particular reference to the medical profession.
10. Chalmers I, Hetherington J, Newdick M, Mutch L, Grant A, Enkin M, Enkin E, Dickersin K. The Oxford database of perinatal trials: developing a register of published reports of controlled trials. Control Clin Trials 1986;7:306–24.
11. Chalmers I, Dickersin K, Chalmers TC. Getting to grips with Archie Cochrane’s agenda. All randomised controlled trials should be registered and reported. BMJ 1992;305:786–8.
12. Cochrane AL, Blythe M. One man’s medicine. An autobiography of Professor Archie Cochrane. London: The British Medical Journal, 1989.
13. Anonymous. Evidence-based medicine, in its place. Lancet 1995;346:785.
14. Feinstein AR, Horwitz RI. Problems in the “evidence” of “evidence-based medicine.” Am J Med 1997;103:529–35.
15. Hill GB. Archie Cochrane and his legacy: an internal challenge to physicians’ autonomy? J Clin Epidemiol 2000;53:1189-92.

Reference as: Robbins RA. Profiles in medical courage: evidence-based medicine and Archie Cochrane. Southwest J Pulm Crit Care 2012;5:65-73. (click here for a PDF version of the manscript)

Profiles of Medical Courage: The Courage to Experiment and Barry Marshall

“The greatest obstacle to knowledge is not ignorance, it is the illusion of knowledge.”-Daniel Boorstein

Previously, four rather obscure physicians and their courageous acts have been described in this series. Barry Marshall is hardly obscure. Along with Robin Warren he won the 2005 Nobel Prize in Medicine for the discovery that H. pylori was the major cause of ulcers.  He has been the subject of numerous articles and interviews. However, his story is so compelling and his courage so remarkable, that it bears repeating.

Figure 1.  Barry Marshall (left) and Robin Warren (right) toasting their 2005 Nobel Prize.

Barry Marshall was an obscure medicine resident (registrar) in Perth, Australia in the early 1980’s. He had an unremarkable career as a medical student and as a resident (1). He was working 14 hour days, was married with 4 children, and his wife was finishing her degree in psychology.

Against this hectic background, he took a 6 month gastroenterology rotation during the later half of 1981. As part of his training, he was encouraged to perform a clinical research project each year and asked his supervisor, Dr Tom Waters, if there was a gastroenterology project he could work on. Waters showed him a letter from Robin Warren, a pathologist, which listed patients with curved bacteria present on their stomach biopsies and asked for someone to clinically follow-up the patients. This was radical stuff in the day. Stomachs were thought to be sterile because the acid killed any bacteria. Marshall was especially interested because one of the patients was a woman he had seen on the ward, who had severe stomach pain but no diagnosis. In desperation Marshall had referred her to a psychiatrist and commenced antidepressant medication for want of a better treatment. The only abnormal finding was some redness in the stomach and bacteria on the stomach biopsy.

He went to visit Warren in the basement of Royal Perth Hospital where the Pathology Department was located. It was to be the first of many afternoon visits during the next year. Warren used to drink strong black coffee and smoke small cigars. Marshall also occasionally indulged. Together they would discuss their research while smoking cigars in the in Warren’s office in the basement.

At the end of 1981, Marshall’s gastroenterology rotation was finished and his rotations for 1982 had been assigned. In the midst of his time in training, Marshall continued his research by fitting it around his other duties. It was a particularly frustrating time. Marshall was attempting to culture the bacteria, and although masses of bacteria were seen on the silver stain of the gastric biopsies, cultures showed no growth. However, fate intervened. A methicillin-resistant Staphylococcus aureus (MRSA) outbreak occurred on one of the wards at Royal Perth. Patients were being quarantined and surveillance cultures were being performed on all staff that had been anywhere near the affected ward. One of Marshall’s research gastric biopsies taken on the Maundy Thursday before Easter of 1982 was sent to the microbiology lab as usual. However, the lab was overwhelmed with MRSA cultures and the Easter holiday.  There was no time to examine Marshall’s cultures on the Saturday before Easter as normally would have been done. The culture plates remained in the incubator, untouched, from Thursday until the following Tuesday. Small transparent colonies were present on the plates and these proved to be a rather pure culture of a Gram negative rod. Why previous cultures showed no growth was explained when Marshall learned the laboratory staff had been processing his research cultures identically to the routine method used for throat-swab cultures. If nothing was seen on the Petri dish after 48 hours, the cultures were discarded. Prior to this, Marshall had no idea that the cultures were only being incubated for 48 hours.

Now that the bacteria had been cultured, Marshall devised a 100 patient observational study of the culture results along with clinical and demographic data. He chose 100 patients simply because in the days before computer spreadsheets this allowed percentages to be easily calculated. He would stay at the hospital each evening to interview inpatients that were due for endoscopy the next morning. In the morning Marshall would arrive early so he could interview the new outpatients as they were being prepared for their endoscopies. Marshall completed his studies in May, 1982 shortly before assuming his next 6 month residency assignment at Port Hedland, a mining town 1,900 km from Perth. In a frenzied weekend while his wife was packing for the trip, Marshall spent Saturday morning at the gastroenterology department photocopying the 100 endoscopy reports.

According to Marshall the time in Port Hedland was an important period. He was able to score the patients’ endoscopies for the presence or absence of ulcers. He had time to do an extensive literature research and discovered that the curved bacteria described by Warren had been described many times before but ignored. Furthermore, he could find no evidence for the existence of stress in causing ulcers. He also had time to digest the results of his study and prepare it for presentation.

In October, 1982, Marshall presented his findings to the local College of Physicians meeting, where it received a mixed response (Figure 2) (1).

Figure 2. Percentage of patients with bacteria identified on gastric biopsy and their endoscopic appearance.

Marshall’s unrestrained enthusiasm, combined with his youthful appearance and informal manner, apparently fed the skepticism of his audience. Marshall's critics contended that the presence of bacteria in the stomachs of patients with gastric diseases was coincidental, and that the bacteria were probably harmless. Furthermore, the bacteria were seen in the stomach and probably could not explain duodenal ulcers. Lastly, it seemed pretty unlikely that a medicine resident was making a significant observation when previously no one thought the bacteria were important.

At about the same time, Marshall found that his contract at Royal Perth would not be renewed for the following year. Previously unfocused, he now wanted to work in gastroenterology or microbiology and continue his research. However, jobs at Royal Perth were not available. Fate intervened for a second time when Marshall was approached by Drs. Norm Marinovich and Ian Hislop at Fremantle Hospital in Perth who offered Marshall a senior registrar position and continued funding of his research. Fremantle was the third and smallest of the teaching hospitals in Perth but had a tradition of openness and experimentation. In the next two years at Fremantle Marshall had an enthusiastic group of collaborators including Ian Hislop, Norm Marinovich, Harvey Turner, David McGechie, Ross Glancy, Neil Noakes, Graeme Francis, Peter Rogers, Neil Stingemore, and importantly, Peter Smith, the chief (superintendent) of medicine.

While at Fremantle, Marshall was able to confirm that the stomach bacteria observed at Royal Perth Hospital also occurred at Fremantle. Furthermore, nearly all peptic ulcer patients had the organism. Freemantle Hospital was supporting Marshall’s work and there Marshall devised the first effective treatment for peptic ulcer disease consisting of antibiotics and bismuth. However, acceptance of the association of the bacteria with peptic ulcer disease was slow. Practitioners of gastroenterology and the pharmaceutical industry were both heavily invested in the theory that peptic ulcers were caused by emotional stress and stomach acids, and could only be treated with repeated courses of antacid medication. While the reduction of stomach acid often alleviated the existing ulcer, inflammation of the stomach lining usually persisted, and most patients found themselves returning in a year or two with another ulcer. Patients were routinely advised to seek psychiatric counseling, find less demanding employment or make other drastic lifestyle changes to address the purported cause of their disease. Volumes were published detailing the alleged psychological causes of gastric ailments, and ulcers remained a frequently cited example of psychosomatic illness.

In 1983 the Gastroenterological Society of Australia meeting was in Perth. This was great news to Marshall because it provided an opportunity to present his research with little cost. He was so poor he could not afford an airfare to any scientific meetings. He submitted an abstract to the meeting, but to his shock, it was rejected (Figure 3).

 

Figure 3. Rejection letter of Marshall’s abstract from the Gastroenterogical Society of Australia meeting held in Perth, 2003.

Sixty-seven abstracts had been submitted and 56 were accepted. The Society suggested that Marshall should seek critical review from his colleagues.

The rejection may have been fortunate because in prompted David McGechie from Fremantle to put Marshall in contact Dr Martin Skirrow in the UK. Skirrow arranged for Marshall to present at the European Campylobacter Meeting in September, 1983. There Marshall’s abstract meant with some acceptance and more publicity. In addition to his presentation, Marshall visited Martin Skirrow in Worcester, England, and attended an endoscopy session at the Worcester Infirmary. Martin's registrar, Cliodna McNulty, was able to successfully isolate the stomach bacteria 3 days later, showing that the spiral organism was not merely an Australian phenomenon but was present in ulcer patients in the UK as well.

After the pilot study was completed, Marshall and Warren submitted their work to the medical journal, The Lancet. Editors were initially reluctant to publish their work because they could find no reviewers who believed their results. Skirrow, contacted The Lancet confirming Warren and Marshal’s findings and, in June 1984, they succeeded in publishing their paper (3).

Despite some success, the time at Fremantle was also frustrating. Marshall’s attempts at making an animal model of peptic ulcer disease were unsuccessful. Furthermore, his research was not receiving the type of attention he had hoped. Criticism had become personal. One prominent gastroenterologist dismissed him as "a crazy guy saying crazy things” (4). His wife overheard comments that were disheartening.

Marshall became convinced that in order to have anyone believe an infectious cause he would have to fulfill Koch’s postulates. However, with the absence of an animal model complicating progress, Marshall decided that he could use himself as a model. Fortunately, he was secretive about the experiment. It is unlikely that any human experimentation committee would have approved. Since he probably would have proceeded anyway, Marshall would likely have been fired. Marshall thought that if he was successful he would develop an ulcer or stomach problems from the bacteria probably in a couple of years. Without explanation he asked Ian Hislop to do a baseline endoscopy and a gastric biopsy. As Hislop put the scope down he said, “Barry, I’m not going to ask why I’m doing this.” (5). From around the gastroscope, Marshall gritted out, “Just take the biopsy.” (5). The endoscopy was normal and the biopsy did not show bacteria.

Then Marshall drank bacteria that were cultured from a patient who did not actually have ulcers, just indigestion and gastritis. Furthermore, Marshall was able to eradicate the patient’s infection with antibiotics, so he already knew that he could, if necessary, take a treatment that worked. Instead of being perfectly well and having a silent infection, he started vomiting after about five days. It was a clear liquid, and there was no acid in it. His wife noticed he was ill and questioned him about it. He told her the truth and she was horrified that he infected himself and took the chance of spreading the infection to her and their kids. She demanded he take an antibiotic. He took the antibiotics and was cured but not before getting another endoscopy and biopsy. He had gastritis and bacteria were everywhere. He had fulfilled Koch’s postulates for gastritis, though not for ulcers. Marshall’s self-experimentation was later immortalized by the comic Ulcer Tales which was distributed to many US physicians (Figure 4) (6).

Figure 4. Ulcer Tales, a comic depicting Marshall’s ingestion of Helicobacter.

Even though he was not officially collaborating with Dr. Warren while he was working at Fremantle Hospital in 1983–84, Marshall and Warren met to discuss the papers they were writing for the Lancet and would meet for dinner with their wives. At one of these dinners Marshall described his self-experimentation. Early the next morning Warren had a call from a journalist in the USA at 5 AM. When asked the usual question about "How do you know it's a pathogen and not a harmless commensal?" Warren blabbed the results of Marshall’s self-experimentation. What Warren did not know was that the journalist was from the "Star" newspaper, the grocery store tabloid. This was right up their alley. In the next issue the story appeared, "Guinea-pig doctor discovers new cure for ulcers ... and the cause” (7).

This became one of those serendipitous, life changing events in Marshall’s life. After the Star article appeared, Marshall was continuously contacted by patients in the USA who read the story and were desperate for treatment. Marshall was able to help. He was treating patients by proxy in the USA as early as 1984. The publicity caught the eye of Mike Manhart, a microbiologist working for Proctor and Gamble in the USA. He tracked down Marshall’s publications and realized the economic potential for P & G who made a bismuth drug. It led to Marshall to leave Perth and spending the next ten years spent at University of Virginia.  

The tide of acceptance began to turn in the early 1990s. By then Marshall could attend a meeting and receive as much praise as criticism. In February 1994 the NIH held a consensus meeting in Washington DC which ended after 2 days with the statement that the key to treatment of duodenal and gastric ulcer was detection and eradication of Helicobacter pylori (8).

However after 10 years in the US, Marshall and his wife decided it was time to go home. Marshall was awarded the McFarlane Burnet Fellowship which funded his lab at the University of Western Australia allowing him to return to Perth. His worked culminated with Robin Warren and him receiving the Nobel prize in 2005. In typical fashion, Marshall acknowledges those who failed to recognize H. pylori in his autobiography (1). Without them Marshall would have had a very different career. He also notes that one of the truly great things about winning the Nobel Prize in 2005 was that he got to share it and celebrate with those who had been involved in the initial work at Royal Perth and Fremantle Hospital. The Australians might refer to this as “partying with your mates”.

There were many occasions when Marshall was lucky: his meeting with Robin Warren, the MRSA outbreak leading to the first culture of the bacteria, the rejection of his abstract in 1983 and chance meetings with many people who helped and collaborated with him. We should remember Marshall not as much for his good fortune or his brashness in self-experimentation, but in his persistence in challenging the dogma that stomachs are sterile and ulcers result from stress. Marshall continues to lecture and because of his fame some of these lectures are available as videos on the internet. He opened his Nobel prize lecture with the quote from Boorstein that began this article, “The greatest obstacle to knowledge is not ignorance, it is the illusion of knowledge.”(7). It fits Marshall’s story well.

Richard A. Robbins, MD

Editor, Southwest Journal of Pulmonary and

   Critical Care 

References

1. Marshall BJ. Autobiography. Available at Nobelprize.org http://www.nobelprize.org/nobel_prizes/medicine/laureates/2005/marshall-autobio.html (accessed 6/5/2012).
2. Marshall BJ. Lecture by Barry Marshall.  http://www.nobelprize.org/mediaplayer/index.php?id=1721
3. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Marshall BJ, Warren JR. Lancet 1984;1(8390):1311-5.
4. Barry Marshall Biography. http://www.achievement.org/autodoc/page/mar1bio-1 (accessed 6/5/2012).
5. Barry Marshall gastroenterologist. http://www.science.org.au/scientists/interviews/m/marshall.html#Childhoodleanings (accessed 6/5/2012).
6. http://www.melanievillines.com/samples/HPComic.pdf (accessed 6/5/2012).
7. Marshall BJ. Nobel Prize Lecture. http://www.docstoc.com/docs/77029428/Barry-Marshall-Nobel-Lecture (accessed 6/5/2012).
8. http://consensus.nih.gov/1994/1994HelicobacterPyloriUlcer094html.htm (accessed 6/5/2012).

Reference as: Robbins RA. Profiles of medical courage: the courage to experiment and Barry Marshall. Southwest J Pulm Crit Care 2012;5:12-19. (click here for a PDF version of the manuscript)

Profiles in Medical Courage: Joseph Goldberger, the Sharecropper’s Plague, Science and Prejudice

“You must accept the truth from whatever source it comes”. -Maimonides

The Sharecropper’s Plague

In the early half of the twentieth century a mysterious disease, “the sharecropper’s plague”, reached epidemic proportions in the Southern US (1). Each state decided whether it would recognize and publicly admit the existence of what was then considered an embarrassment. The total number of new annual cases was estimated as about 75,000 in 1915 and about 100,000 throughout the 1920s (2). The disease had a 40% mortality rate, and many survivors with dementia were confined to mental institutions (3). Patients initially presented with symmetrically reddened skin, similar to that produced by a sunburn or poison oak. Later, the dermatitis turned rough and scaly in one or more locations, such as the hands, the tops of the feet, or the ankles, or in a butterfly-shaped distribution across the nose. Disturbances of the digestive tract and the nervous system occurred as late manifestations. This led to the plague being characterized by 4 D’s: dermatitis, diarrhea, dementia and death. In case you have not guessed, the “sharecropper’s plague” was pellagra.

“Pellagraphobia" developed as the disease acquired a social stigma that left victims and their families ostracized (4). Many hospitals refused admittance to patients with pellagra and many staff refused to care for them. Quarantine was common and elementary schools tried to bar children whose family members had pellagra (5). The cause of the disease was unknown. A number of etiologies were proposed including infection; the eating of moldy corn; inherited susceptibility; heavy exposure to sunlight; and exposure to cottonseed oil (2). There were more than 200 proposed "cures" for pellagra included diet, arsenic, castor oil, quinine, strychnine, and the healing waters of mineral springs (5).

In response the US Surgeon General, Walter Wyman, appointed a seven-man commission headed by Dr. Claude H. Lavinder to find the etiologic agent and perhaps identify an insect vector. Lavinder toured affected areas and established a small laboratory at the South Carolina Hospital for the Insane where he injected rabbits, chickens, and guinea pigs with blood, spinal fluid, and spleen pulp from fatal cases of pellagra, without results. In 1911, he set up a larger laboratory at the Marine Hospital in Savannah and unsuccessfully attempted to transmit the causative agent to monkeys. The Commission conducted a survey of pellagra cases in the cotton mill districts in South Carolina where it was especially common. In its 1914 report, the commission concluded that pellagra had no relation to diet, that it spread most rapidly where sanitary disposal of waste was poorest, and that the disease occurred almost exclusively in people who lived in or next to the house of another person with pellagra (6). The general consensus was that pellagra was likely infectious. These conclusions are not surprising since the early twentieth century was an era when infections were being discovered as the causes of many diseases such as yellow fever, dengue fever, typhus, typhoid fever, lobar pneumonia, tuberculosis, cerebrospinal meningitis, syphilis, cholera, malaria, dysentery, scarlet fever, tetanus, and diphtheria. Pellagra was viewed as just another of those diseases with an as yet undiscovered pathogen.

Goldberger’s Investigations

Human Observations and Dietary Interventions

When Lavinder asked to be reassigned in 1914, he was replaced by Joseph Goldberger.

Figure 1. Dr. Joseph Goldberger

Goldberger spent his first 3 weeks in the South, directly observing patients with pellagra and their living environment. He summarized his observations with a report and hypothesis (8).  He stated that pellagra was: 1) present almost exclusively in rural areas; 2) associated with poverty; 3) associated with a relatively cheap and filling diet consisting of the "three M's", meat (fatback), meal (corn meal), and molasses; and 4) not acquired by nurses, attendants, or employees in hospitals or orphanages whose inpatients had the disease. The last finding seemed particularly incompatible with an infectious cause. Goldberger hypothesized that the staff's peculiar exemption from or immunity to the disease could be explained by a difference in diet.

To prove his hypothesis, Goldberger tried to prevent and cure pellagra by dietary interventions. In two orphanages having high rates of endemic pellagra he identified 172 patients with pellagra and 168 children who were initially free of disease (8). He arranged for both groups of to receive a new, more varied diet, subsidized by Federal funds. The results were evident in just a few weeks: No new cases of pellagra occurred and almost all children with pellagra were cured. After a year, the two orphanages had only one case of recurrent pellagra.

Goldberger then repeated the study in a mental asylum, using a randomized, controlled trial (9). Of 72 patients with pellagra, all were cured after the introduction of the new diet. The treatment group had a high drop-out rate, however, because some patients' mental status improved so greatly that they were permitted to leave the asylum. In the group on the old diet, the recurrence rate of pellagra was almost 50%. Interestingly, when the Federal subsidies expired at the end of these studies, the diets returned to the old three M's diet and 40% of the inmates again developed pellagra.

Goldberger then began a new study to induce pellagra by dietary deprivation (10). In a prison where pellagra had never been reported, a dozen volunteers were promised full pardons at the experiment's end for eating an experimental diet. The diet consisted largely of cereal and included biscuits, gravy, cornbread, grits, rice, syrup, collard greens, and yams. By the end of the 9 month study, 7 of the 12 inmates were diagnosed with pellagra. In all instances, resumption of a better diet resulted in cure.

To refute the theory that pellagra was infectious, Goldberger injected blood from patients with pellagra into the deltoids of healthy volunteers, including himself and his wife (11). He also mixed extracts of skin parings, nasal secretions, urine, and feces from patients with pellagra into a wheat dough concoction that was swallowed by all volunteers. These "filth party" experiments were repeated seven times. No signs of pellagra developed in the volunteers.

Demographic Studies

Goldberger next studied the basic demographics, socioeconomic status, and diet of patients with pellagra (12,13). In these surveys, Goldberger found that a poor year in cotton production was usually followed by an increase pellagra mortality (13). He showed an inverse relationship between socioeconomic status and the incidence of pellagra. Goldberger also found a significant correlation between the rise and fall in the price of animal protein foods and the disease's onset and remission (12,13). These data further supported his hypothesis that pellagra was caused by a dietary deficiency.

Laboratory Studies

Goldberger hypothesized that pellagra was caused by an amino acid deficiency, possibly tryptophan, based on his demographic and human studies. Goldberger soon realized that ordinary yeast contained and was the most potent source of the pellagra-preventive factor in rats and in dogs (14). In 1927 he arranged to have the Red Cross ship large quantities of yeast into flood-stricken areas along the Mississippi river (15). The expected outbreak of pellagra did not occur; instead, the disease fell below its usual seasonal incidence. After the emergency, yeast was no longer provided, and the usual level of pellagra returned to the area. Goldberger died in 1929 before he could find a specific pellagra cure.

In 1937 nicotinic acid or niacin was found to cure pellagra in dogs (16). This finding was soon confirmed for human pellagra (17). The final, almost complete elimination of pellagra dates to the 1940s coinciding with improvements in diet and a requirement by many states to enrich food with vitamins including niacin (18). What provoked the epidemic at the beginning of the twentieth century is not entirely clear. However, changes in the methods of milling corn may have led to the outbreak, because the germ or embryo in the corn kernel is removed in the new milling process begun at the turn of the century. The kernel contains a high proportion of lipid, enzymes, and cofactors, including nicotinic acid (19).

Politics and Pellagra

Goldberger investigations are exceptional. He performed community observation, clinical investigation, and laboratory investigations that led to the elimination of a common health problem. Yet, his extraordinary accomplishments are largely unrecognized. Politics and prejudice seem to be largely responsible for Goldberger’s obscurity.

Politics apparently had great influence on pellagra public policy. An association of pellagra with poverty was clear, and offended Southern pride where the disease was concentrated. When the epidemiologic studies of Goldberger, a Northerner, an immigrant, and a Jew pointed to social and economic factors as being responsible for the occurrence of pellagra, Southern sensitivities were further riled. Editorial pages and speeches by congressmen criticized and condemned such insulting inferences concerning the contentment of the people of the South (2).

When a letter from Goldberger to the Surgeon General describing the extent of pellagra and its relationship to poverty and poor diet reached the press; it stimulated the newly inaugurated president, Warren Harding, to write the Surgeon General asking for a complete report. Harding suggested that the Red Cross provide aid, and offered to ask for a congressional appropriation (2). This infuriated a number of influential Southern politicians including Congressman James F. Byrnes (later U.S. Senator, Secretary of State, and Supreme Court Justice). He called the news reports of "famine and plague" in South Carolina an "utter absurdity," calling for rejection of offers of aid from the Red Cross. A Georgia city wired one of their senators, Tom Watson, "When this part of Georgia suffers from famine, the rest of the world will be dead!" (20). The United Daughters of the Confederacy at first voted to thank President Harding for his concern, but a month later it sent him a letter of protest. "Famine does not exist anywhere in the South," their letter stated, "and we fail to find a general increase in pellagra" (20). Since pellagra was common in Italy, Italian immigrants were blamed for the outbreak of the disease (2). No one seemed to notice that the Italians living in the South did not have pellagra, since they did not favor the meat, meal and molasses diet that led to the disease.

Goldberger’s Legacy

Goldberger died in 1929 of renal cell carcinoma not having convinced public health officials of a dietary cause of pellagra. Goldberger should be remembered not only for his superb investigations but for formulating a hypothesis, testing it and not surrendering to insults of his heritage or religion. Although rarely remembered in medical textbooks, he has been immortalized in some unlikely places including “Real Life Comics” in 1941 (Figure 2).

Figure 2. Joseph Goldberger in “Real Life Comics”.

Figure 2. Joseph Goldberger in “Real Life Comics”.

In some aspects Goldberger’s story is echoed in modern day politics where politicians attempt to manipulate or deny scientific discovery to further their own political careers. Even when Goldberger showed that affordable therapy with yeast cured pellagra, many Southern politicians remained reticent to accept diet as a cause of the disease. Their ambitions undoubtedly contributed to the excess mortality and morbidity of thousands of impoverished Southerners in the early twentieth century.

References

1. Elmore JG, Feinstein AR. Joseph Goldberger: An unsung hero of American clinical epidemiology. Ann Intern Med 1994;121:372-37.
2. Bollet AJ. Politics and pellagra: the epidemic of pellagra in the U.S. in the early twentieth century. Yale J Biol Med 1992;65:211-21.
3. Lavinder CH. The prevalence and geographic distribution of pellagra in the United States. Public Health Rep 1912;27:2076-88.
4. Niles GM. Pellagraphobia: A word of caution. JAMA 1912;58:1341.
5. Etheridge EW. The Butterfly Caste: A Social History of Pellagra in the South. Westport, CT: Greenwood Publishing Company; 1972.
6. Siler JF, Garrison PE, MacNeal WJ. Pellagra, a summary of the first progress report of the Thompson-McFadden Pellagra Commission. JAMA 1914;62:8-12.
7. Parsons RP (1943). Trail to light: A biography of Joseph Goldberger. Bobbs-Merrill. ASIN B0007DYTFM.
8. Goldberger J. The etiology of pellagra: The significance of certain epidemiological observations with respect thereto. Public Health Rep1914;29:1683-86.
9. Goldberger J, Waring CH, Tanner WF. Pellagra prevention by diet among institutional inmates. Public Health Rep 1923;38:2361-68.
10. Goldberger J, Wheeler GA. The experimental production of pellagra in human subjects by means of diet. Hygienic Laboratory Bulletin 1920;120:7-116.
11. Goldberger J. The transmissibility of pellagra: Experimental attempts at transmission to human subjects. Public Health Rep. 1916;31:3159-73.
12. Goldberger J, Wheeler GA, Sydenstricker E. A study of the diet of nonpellagrin and of pellagrin households. JAMA 1918;71:944-9.
13. Sydenstricker E, Wheeler GA, Goldberger J. Disabling sickness among the population of seven cotton-mill villages of South Carolina in relation to family income. Public Health Rep. 1918;33:2038-51.
14. Goldberger JG, Wheeler GA, Lillie RD, Rogers LM. A further study of butter, fresh beef and yeast as pellagra preventives, with consideration of the relation of factor P-P of pellagra (and black tongue of dogs) to vitamin B. Public Health Rep 1926;41:297-318.
15. Goldberger JG, Sydenstricker E. Pellagra in the Mississippi flood area. Public Health Rep 1927;42:2706-25.
16. Elvehjem CA, Madden RJ, Strong FM, Wooley DW. Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J Amer Chem Soc 1937;59:1767.
17. Smith DF, Ruffin JM, Smith SG. Pellagra successfully treated with nicotinic acid: a case report. JAMA 1937;109:2054-5.
18. Wilder RM. A brief history of the enrichment of bread and flour. JAMA 1956;162:1539-40.
19. Carpenter KJ. Effects of different methods of processing maize on its pellagragenic activity. Fed Proc 1981;40:1531-5.
20. Etheridge EW: The Butterfly Caste. A Social History of Pellagra in the South. Westport, CT, Greenwood Press, 1972, 278 pp

Reference as: Robbins RA. Profiles in medical courage: Joseph Goldberger, the sharecropper’s plague, science and prejudice. Southwest J Pulm Crit Care 2012;4:189-93. (Click here for a PDF version of the manuscript)

Profiles in Medical Courage: Peter Wilmshurst, the Physician Fugitive

"Nothing defines human beings better than their willingness to do irrational things in the pursuit of phenomenally unlikely payoffs." -Scott Adams, US humorist, in The Dilbert Principle (1996)

Peter Wilmshurst, a cardiologist in the UK, has taken on medical companies over their honesty not once, but twice. His exciting story illustrates how far companies will go to protect their quest for big bucks and the potential financial risk incurred by honest physicians who do clinical research.

A movie entitled “The Fugitive”, based on the popular 1960’s television series, was released in 1993. The movie and television series both tell the story of Dr. Richard Kimble wrongly accused of murdering his wife and Kimble’s search for the real killer, a one-armed man. In the movie version, Harrison Ford plays Kimble and discovers that the one-armed man, Frederick Sykes, is employed by a pharmaceutical company that is working on a new drug. Kimble had investigated the drug and discovered that it caused liver damage. He also discovers that his friend and associate, Dr. Charles Nichols, who is leading the drug's development, arranged a cover-up, and ordered Sykes to kill Kimble, with Kimble’s wife's death being incidental. This is exciting stuff worthy of a movie. Although the plot was plausible, most of us in medical research thought only barely plausible. Little did we realize that the extent some pharmaceutical companies would go to protect their patented products. After all, we are talking about big bucks here.

Peter Wilmshurst

Amrinone

In 1986, seven years before the release of “The Fugitive”, Dr. Peter Wilmshurst, a cardiologist in the United Kingdom, went to the Guardian Newspaper with a fantastic story regarding the development of a new drug.  Wilmshurst’s research was on heart failure. In the 1980’s there were few treatments to improve symptoms of heart failure patients and none to improve survival. Wilmshurst was offered the opportunity to do research on a promising new drug, amrinone, patented by Sterling-Winthrop. Research showed that the drug increased the strength of heart contraction in animals. To assess its effects in man, a group from Peter Bent Brigham Hospital and Harvard Medical School published in the New England Journal of Medicine the results on the hemodynamic responses to amrinone in 8 patients with heart failure immediately after amrinone infusion (1). Amrinone increased cardiac index and left ventricular end-diastolic pressure fell. No toxicity was observed. To those physicians who care for heart failure patients, this new therapy is exciting stuff. The New England Journal is probably the most influential medical journal in the world. The article came from the cardiology department at Harvard and one of the authors was Eugene Braunwald, the most well known cardiologist in the world at the time and head of medicine at Harvard. However, Wilmshurst research disagreed on the effects of amrinone with Braunwald’s findings. In a large series of experiments Wilmshurst group showed that amrinone did not affect contractility in patients with heart failure. Furthermore, life threatening side effects were frequent (2,3).

Wilmshurst reported his findings to Sterling-Winthrop. According to Wilmshurst, Sterling-Winthrop employees asked him to exclude the patients with a downward trend in contractility. When Wilmshurst refused he was threatened with litigation (4). Wilmshurst proceeded with publication of his results in abstracts and meeting presentations but his on-going research studies on amrinone ended when Sterling-Winthrop employees removed the drug stocks from the pharmacy (4).

A number of incidents occurred apparently to prevent presentation or discredit Wilmshurst’s research. One strange incident involved one of Wilmshurst’s colleagues, Alex Crowther, who was due to present Wilmshurst’s and his work on amrinone on the second day of a meeting in Luxembourg (4). When Crowther arrived he discovered that his talk had been rescheduled for the previous day. The organizers had received a forged letter that appeared to be from him asking for his talk to be brought forward a day.

When Wilmshurst presented his findings on side effects at another meeting, a Sterling-Winthrop employee stood up and said that he had made up the findings (4).  At other meetings, three professors of cardiology, each of who was a paid consultant to Sterling-Winthrop, made public statements that they had tried to replicate Wilmshurst’s findings and failed (4). At one point, Wilmshurst was asked to meet with representatives from Sterling-Winthrop and a different professor of cardiology. They assured Wilmshurst he was mistaken about the drug. The cardiologist said that he was aware of findings by other investigators and that these entirely refuted Wilmshurst’s data. He advised that Wilmshurst should not publish any more of his findings. He said that we would be found to be wrong and his reputation would be adversely affected.

The Netherlands Committee for the Evaluation of Medicines reviewed Wilmshurst’s paper on the side effects of amrinone (6). There were major discrepancies when compared with the clinical record cards submitted to the evaluation committee by Sterling-Winthrop compared to the findings published by Wilmshurst.  Wilmshurst showed that Sterling-Winthrop had sent the Netherlands Committee falsified clinical records on his patients with the information on adverse events deleted.

Because of these discrepancies, Wilmshurst contacted the UK Committee on Safety of Medicines (CSM) and discovered that Sterling-Winthrop had also failed to notify CSM of the side effects observed in his patients (4). Furthermore, Sterling-Winthrop had not obtained a Clinical Trials Certificate for oral amrinone, though they had for the amrinone injection (4). When Wilmshurst raised this with the Sterling-Winthrop, he was told that Sterling-Winthrop executives had told the UK Government that if the company was prosecuted it would close its large manufacturing plant in the UK. Wilmshurst also contacted the Association of the British Pharmaceutical Industry, the Faculty of Pharmaceutical Medicine of the Royal College of Physicians and the General Medical Council, none of whom were interested (4). Wilmshurst spoke to editors of medical journals, including BMJ, Lancet and Nature. Although none disputed the facts, all were afraid to take on a multinational pharmaceutical company with comparatively unlimited financial and legal resources.

While this was going on, Sterling-Winthrop told a hearing of the USA’s Food and Drugs Administration that there had been over 1400 serious adverse events in 1200 patients given amrinone in trials and they would cease trials and applications for product licenses worldwide. Yet Sterling-Winthrop continued to market the drug in several third world countries (4). It was at this time Wilmshurst contacted James Erlichman, a Guardian reporter. Erlichman’s paper covered the story on the front, back and the whole of an inside page of one issue and in follow-up stories in other issues (4). Sterling-Winthrop withdrew the oral version of the drug world wide in 1986 (4). This is exciting stuff and could have been the plot for a movie. For his efforts Wilmshurst was awarded the HealthWatch Award in 2003 (7).

MIST Trial

Wilmshurst’s experience may have served him well in knowing the lengths commercial companies will go to protect their patented products. In 2000 he published an interesting observation suggesting a relationship between the repair of patent foramen ovale (PFO) and the cure or reduction of migraines (8). PFO is a flap-like opening in the atrial septum of the heart, is the most common cause of a right to left shunt, and associated with an increased risk of migraine. As many as one person in four has a PFO (9). The research interested NMT Medical, a small, start-up medical device company based in Boston which manufactured a percutaneously inserted PFO closure device called STARFlex. NMT was planning a trial to see if their device would relief migraine in those with a PFO. The trial, eventually named the Migraine Intervention with STARFlex Technology (MIST) and Wilmshurst seemed the perfect partner for NMT. He had published in the area and was known as an ethical physician who had won the HealthWatch award (10). NMT estimated that a target population of 3.8 million migraine sufferers and the financial opportunity to be in excess of $15 billion (11). NMT was riding high with a stock price approaching $25/share. We are talking big bucks here and this must have been exciting stuff to NMT executives.

The trial ran from during 2005. However, who should conduct the final, post-procedure transthoracic echocardiograms, the implanting cardiologists or echocardiography specialists, was unclear. The echocardiograms would ensure that the STARFlex device had closed the shunts. Wilmshurst, who was not one of the trial’s implanting cardiologists, says he had argued from the outset for a central echocardiography core laboratory, however, NMT proceeded with having the implanting cardiologists read the echocardiograms. A compromise was reached. Wilmshurst would review the final echocardiograms. In contrast to the implanting cardiologists who interpreted the echos to indicate that only four of 65 patients had moderate or large residual shunts, Wilmshurst reported that more than a third had a significant residual shunt.

Wilmshurst’s results were potentially devastating to NMT with the efficacy of their device being called into question. NMT organized a second review which also identified over a third of the patients with residual shunt although most were classified as pulmonary rather than atrial shunts (10). When the paper was published in 2008, an accompanying editorial in Circulation stated “The lack of an established independent core laboratory for echocardiographic data analysis must haunt the trial investigators.” (13).

The results of the MIST trial were announced at the American College of Cardiology meeting in March, 2006. Although the study found “an approximate 37% reduction in migraine burden in those patients who received a STARFlex implant and a 17% reduction in those who received the sham procedure,” it had failed to reach a significant difference in its primary end point, eliminating migraines (12). Based on previous observational studies, including Wilmshurst’s, researchers had expected migraine to have stopped in 40% of the treatment group at six months compared with 15% in the control group (13).

Publication Dispute

Matters came to a head when Wilmshurst attended the Transcatheter Cardiovascular Therapeutics Conference in Washington, October 25-27, 2007. According to Wilmshurst, it had been agreed that he would make presentations about the trial at cardiac meetings and Andrew Dowson, the other PI on the MIST trial, would present the data at neurology meetings. However, Wilmshurst was surprised when he discovered Dowson was scheduled to present the MIST trial data at the cardiology meeting. In the course of giving a separate talk on patent foramen ovale and migraine at the same meeting, Wilmshurst mentioned the MIST trial. At the session was Shelley Wood, a writer for TheHeart.org, who realized there was disagreement about the rate of residual shunts and interviewed Wilmshurst. Her article published October 26 during the meeting quotes Wilmshurst as alleging that NMT lied about whether echocardiograms from the MIST patients have been independently reviewed, and massaged the data to portray its STARFlex device in the best possible light (15). The article also quotes an NMT spokesperson, who says Wilmshurst was "on a warpath" and was never really the co-principal investigator for MIST. Furthermore, the NMT spokesman claimed Wilmshurst had been dropped from the trial for committing protocol violations. Wilmshurst claims he committed no protocol violations. This must have been exciting stuff to those who relish a controversy in medicine.

 Libel Suit

Less than two weeks after returning from Washington, Wilmshurst received a letter from UK solicitors acting for NMT, accusing him of having made “seriously defamatory allegations” in the interview he had given to TheHeart.org (10). According to the solicitors, NMT “has a reputation in this jurisdiction which it cannot permit to be tarnished by [Wilmhurst’s] serious and unjustified libels upon it.” NMT sued Dr. Wilmshurst for libel in the UK during December 2007. Subsequently, three more suits were filed over the next few years.

NMT did not sue TheHeart.org or Shelley Wood who reported Wilmhurst’s comments. This may be because the suit would need to be filed in the US and American courts are highly protective of free speech rights under the US Constitution. However, the UK libel laws differ in several aspects from the US and have several provisions that favor the plaintiff (16):

1. The onus of proof is on the defendant.
2. Legal fees are usually considerably greater than the damages that might be awarded. In other words, even if the defendant wins he may have a considerable financial loss. 
3. Lawyers fees are often not contingent on winning in the UK. 
4. Trials are long often placing considerable financial hardship on the defendant.
5.  There is no compensation for personal cost, such as time wasted and earnings lost by spending time dealing with the case.
6. “Libel tourism” is permitted, so that wealthy foreign individuals or corporations are allowed to sue in the UK but are themselves immune to actions brought against them in the UK.

Wilmshurst’s libel case created some attention in the UK. Wilmshurst was asked to appear on BBC 4’s morning radio program (for which he was sued again by NMT) and even called to the office of the UK Minister of Justice to discuss his case. Several medical journals picked up on the case, most notably the British Medical Journal which published a 4 page review in January, 2010 (10). The perception was that an American corporation was using the UK courts to suppress a UK physician from telling the truth resulted in a call for libel reform in the UK (17). This is exciting stuff.

Circulation Correction

Over a year after publication of the MIST trial in August, 2009 Circulation published a 700 word correction (18). The correction notes that Dr. Peter Wilmshurst did not sign the Copyright Transfer Agreement because of an internal disagreement about the conduct of study. According to Wilmshurst the correction contains information regarding device embolization which had not been disclosed in the original paper, but there is no mention of several of Wilmshurst’s other concerns, including the alleged conflicts of interest of some authors of the paper and the two echocardiogram reviews (16).

CLOSURE I Trial

In January 2008, NMT announced it was closing its follow-up MIST trial in the US. Although the company denied that failure of the first trial was the reason for cancellation, they did note that the trial had become “an expensive endeavor with little likelihood of being completed in a reasonable timeframe.” (10). Costs of the trial were estimated at $14 million and instead NMT decided to focus its resources on a trial designed to evaluate the effectiveness of PFO closure by STARFlex as a treatment for stroke compared with existing medical therapy, the CLOSURE I trial.  However, like the MIST trial the results of the CLOSURE trial were disappointing (19). The rates of stroke or TIA were no different between those who had the STARFlex device inserted and anticoagulant therapy.  

Financial Fallout

The results of the CLOSURE I were obviously distressing financial news for NMT. NMT’s stock which had been as high as $25/share had decreased to $0.25/share after announcement of the CLOSURE I trial.

Apparently legal trials move as slowly in the UK as in the US. In the three years that had elapsed since filing of the initial the suit and the announcement of the CLOSURE I results, no legal action was taken, although legal expenses continued to accumulate (16). Wilmshurst had accrued over $150,000 in out of pocket expenses and was in danger of losing his house. The anticipated trial costs were estimated at over $5 million for each side and would have required Wilmshurst to be in court for about 6 months. Obviously this would be both financially and professionally ruinous to Wilmshurst. Predictably, NMT filed for bankruptcy in April, 2011 but not before filing the fourth libel action against Wilmshurst in March. The bankruptcy filing ended the legal actions against Wilmshurst. 

Wilmshurst’s Account

After the bankruptcy filing, Wilmshurst published a summary of his experience in Radical Statistics (16). In this article Wilmshurst points out that while the data supporting the STARFlex device was unfavorable, NMT’s website and annual report did not reflect the data. On a rotating banner on the website and in the annual report were the names and photographs of the three patients who had a STARFlex implant and who were free of migraine. Wilmshurst points out that an important question is how NMT came to make contact with the three patients.

Wilmshurst said “My experience suggests that corporations can use the English defamation laws to misrepresent the results of clinical research. A corporation can propagate a misleading version and can use the defamation laws to bully those who object into remaining silent.” (16). He goes on to say “The law courts are not the best way to determine scientific truth. Few judges and even fewer juries have the training to weigh scientific evidence. An adversarial system is not the appropriate way, particularly when it pits an ordinary individual with limited financial resources against expensive barristers employed by corporations with more money. Truth should not be decided by those with greatest wealth using bullying and threats to make a scientist retract what he or she knows is true.”

We should remember Peter Wilmshurst for his courage in standing up for the truth, not once but twice. However, given our system and the comparatively large financial resources of corporations, physicians do so at their own professional and financial peril. Some such as the UK not for profit group, Libel Reform, seek to change the UK libel laws to prevent incidents such as Wilmshurst’s.  Many physicians both in the UK and US likely agree that the exciting stuff experienced by Wilmshurst do not need to happen when a physician stands up for the truth. However, this is doubtful in the absence of real legal reform. After all, we are talking about big bucks here.  

References

1. Benotti JR, Grossman W, Braunwald E, Davolos DD, Alousi AA. Hemodynamic assessment of amrinone. N Engl J Med 1978;299:1373-7.
2. Wilmshurst PT, Walker JM, Fry CH, et al. Inotropic and vasodilator effects of amrinone on isolated human tissue. Cardiovasc Res 1984,18:302-9.
3. Wilmshurst PT, Thompson DS, Juul SM, Dittrich HC, Dawson JR, Walker JM, Jenkins BS, Coltart DJ, Webb-Peploe MM. Effects of intracoronary and intravenous amrinone infusion in patients with cardiac failure and patients with near normal cardiac function. Br Heart J 1985;53:493-506.
4. Erlichman J. Drug firm "made threats". Company tested heart drug with DHSS clearance. The Guardian 3rd November 1986; 1 and 6.
5. B Massie, M Bourassa, R DiBianco, M Hess, M Konstam, M Likoff, M Packer. Long-term oral administration of amrinone for congestive heart failure: lack of efficacy in a multicenter controlled trial. Circulation 1985,71:963-971.
6. Wilmshurst PT, Webb-Peploe MM. Side-effects of amrinone therapy. Br Heart J 1983;49:447-51.
7. http://www.healthwatch-uk.org/awardwinners/peterwilmshurst.html
8. Wilmshurst P, Nightingale S, Walsh K, Morrison W. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet 2000;356:1648-51.
9. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59:17-20.
10. Gornall J. A very public break-up. BMJ 2010;34:180-3.
11. PR Newswire. NMT Medical initiates patient enrollment in migraine headache study, expects earlier completion. Press release, January 7, 2005. http://www.advfn.com/news_NMT-Medical-Initiates-Patient-Enrollment-in-Migraine-Headache-Study-Expects-Ear_9896513.html
12. Dowson A, Mullen MJ, Peatfield R, Muir K, Khan AA, Wells C, et al. Migraine intervention with STARFlex Technology (MIST) trial. Circulation 2008;117:1397-404.
13. Carroll J. A controversial trial of migraine and patent foramen ovale closure. Circulation 2008;117:1358-60.
14. Nugent AW, Britt A, Gauvreau K, Piercey GE, Lock JE, Jenkins KJ. Device closure rates of simple atrial septal defects optimized by the STARFlex device. J Am Coll Cardiol 2006;48:538-44.
15. Wood S. Co-PI of MIST trial alleges data mismanagement, misinformation. TheHeart.org. October 26, 2007. http://www.theheart.org/article/821779.do
16. Wilmshurst P. The effects of the libel laws on science-a personal experience. Rad Stats 2011;104:1-10. 
17.  http://www.libelreform.org/
18. Correction for Dowson et al. Circulation 2009; DOI: DOI: 10.1161/CIRCULATIONAHA.109.192626. Available at: http://circ.ahajournals.org
19. Wood S. CLOSURE I: No overall benefit, no reduction in stroke or TIA with PFO closure. TheHeart.org. November 15, 2010. Available at: http://www.theheart.org/article/1149945.do
20. Sample I. Setback for US company suing cardiologist Peter Wilmshurst for libel. The Guardian. December 1, 2010. Available at: http://www.guardian.co.uk/science/2010/dec/01/company-suing-peter-wilmshurst-libel
21. http://www.libelreform.org/news/492-a-british-cardiologist-sued-by-an-american-medical-company-for-a-canadian-article

Acknowledgements

The author is indebted to Michael Garrett MD who suggested Dr. Wilmshurst as a subject for Profiles in Medical Courage and Peter Wilmshurst who reviewed the manuscript.

Referece as: Robbins RA. Profiles in medical courage: Peter Wilmshurst, the physician fugitive. Southwest J Pulm Crit Care 2012;4:134-41. (Click here for a PDF version of the posting)