He was right, in the narrow sense, that no one had yet proven a causal link between smoking and cancer:
While most of the afflictions that had been killing British citizens for centuries were trending downward, the result of advances in medicine and sanitation, one disease was killing more and more people each year: carcinoma of the lung.
The figures were staggering. Between 1922 and 1947, the number of deaths attributed to lung cancer increased 15-fold across England and Wales. Similar trends were documented around the world. Everywhere, the primary target of the disease seemed to be men.
What was the cause? Theories abounded. More people than ever were living in large, polluted cities. Cars filled the nation’s causeways, belching noxious fumes. Those causeways were increasingly being covered in tar. Advances in X-ray technology allowed for more accurate diagnoses. And, of course, more and more people were smoking cigarettes.
Which of these factors was to blame? All of them? None of them? British society had changed so dramatically and in so many ways since the First World War, it was impossible to identify a single cause. As Fisher would say, there were just too many confounding variables.
In 1947, the British Medical Research Council hired Austin Bradford Hill and Richard Doll to look into the question.
Though Doll was not well known at the time, Hill was an obvious choice. A few years earlier, he had made a name for himself with a pioneering study on the use of antibiotics to treat tuberculosis. Just as Fisher had randomly distributed fertilizer across the fields at Rothamsted, Hill had given out streptomycin to tubercular patients at random while prescribing bed rest to others. Once again, the goal was to make sure that the patients who received one treatment were, on average, identical to those who received the other. Any large difference in outcomes between the two groups had to be the result of the drug. It was medicine’s first published randomized control trial.
Despite Hill’s groundbreaking work with randomization, the question of whether smoking (or anything else) causes cancer was not one you could ask with a randomized control trial. Not ethically, anyway.
“That would involve taking a group of say 6,000 people, selecting 3,000 at random and forcing them to smoke for 5 years, while forcing the other 3,000 not to smoke for 5 years, and then comparing the incidence of lung cancer in the two groups,” says Donald Gillies, an emeritus professor of philosophy of science and mathematics at University College London. “Clearly this could not be done, so, in this example, one has to rely on other types of evidence.”
Hill and Doll tried to find that evidence in the hospitals of London. They tracked down over 1,400 patients, half of whom were suffering from lung cancer, the other half of whom had been hospitalized for other reasons. Then, as Doll later told the BBC, “we asked them every question we could think of.”
These questions covered their medical and family histories, their jobs, their hobbies, where they lived, what they ate, and any other factor that might possibly be related to lung cancer. The two epidemiologists were shooting in the dark. The hope was that one of the many questions would touch on a trait or behavior that was common among the lung cancer patients and rare among those in the control group.
At the beginning of the study, Doll had his own theory.
“I personally thought it was tarring of the roads,” Doll said. But as the results began to come in, a different pattern emerged. “I gave up smoking two-thirds of the way though the study.”
Hill and Doll published their results in the British Medical Journal in September of 1950. The findings were alarming, but not conclusive. Though the study found that smokers were more likely than non-smokers to have lung cancer, and that the prevalence of the disease rose with the quantity smoked, the design of the study still left room for Fisher’s dreaded “confounding” problem.
The problem was in the selection of the control. Hill and Doll had picked a comparison group that resembled the lung cancer patients in age, sex, approximate residence, and social class. But did this cover the entire list of possible confounders? Was there some other trait, forgotten or invisible, that the two researchers had failed to ask about?
To get around this problem, Hill and Doll designed a study where they wouldn’t have to choose a control group at all. Instead, the two researchers surveyed over 30,000 doctors across England. These doctors were asked about their smoking habits and medical histories. And then Hill and Doll waited to see which doctors would die first.
By 1954, a familiar pattern began to emerge. Among the British doctors, 36 had died of lung cancer. All of them had been smokers. Once again, the death rate increased with the rate of smoking.
The “British Doctor Study” had a distinct advantage over the earlier survey of patients. Here, the researchers could show a clear “this then that” relationship (what medical researchers call a “dose-response”). Some doctors smoked more than others in 1951. By 1954, more of those doctors were dead.
The back-to-back Doll and Hill studies were notable for their scope, but they were not the only ones to find a consistent connection between smoking and lung cancer. Around the same time, the American epidemiologists, E. C. Hammond and Daniel Horn conducted a study very similar to the Hill and Doll survey of British doctors.
Their results were remarkably consistent. In 1957, the Medical Research Council and the British Medical Journal decided that enough evidence had been gathered. Citing Doll and Hill, the journal declared that “the most reasonable interpretation of this evidence is that the relationship is one of direct cause and effect.”
Ronald Fisher begged to differ.
In some ways, the timing was perfect. In 1957, Fisher had just retired and was looking for a place to direct his considerable intellect and condescension.
Neither the first nor the last retiree to start a flame war, Fisher launched his opening salvo by questioning the certainty with which the British Medical Journal had declared the argument over.
“A good prima facie case had been made for further investigation,” he wrote. “The further investigation seems, however, to have degenerated into the making of more confident exclamations.”
The first letter was followed by a second and then a third. In 1959, Fisher amassed these missives into a book. He denounced his colleagues for manufacturing anti-smoking “propaganda.” He accused Hill and Doll of suppressing contrary evidence. He hit the lecture circuit, relishing the opportunity to once again hold forth before the statistical establishment and to be, in the words of his daughter, “deliberately provocative.”
Provocation aside, Fisher’s critique came down to the same statistical problem that he had been tackling since his days at Rothamsted: confounding variables. He did not dispute that smoking and lung cancer tended to rise and fall together—that is, that they were correlated. But Hill and Doll and the entire British medical establishment had committed “an error…of an old kind, in arguing from correlation to causation,” he wrote in a letter to Nature.
Most researchers had evaluated the association between smoking and cancer and concluded that the former caused the latter. But what if the opposite were true?
What if the development of acute lung cancer was preceded by an undiagnosed “chronic inflammation,” he wrote. And what if this inflammation led to a mild discomfort, but no conscious pain? If that were the case, wrote Fisher, then one would expect those suffering from pre-diagnosed lung cancer to turn to cigarettes for relief. And here was the British Medical Journal suggesting that smoking be banned in movie theaters!
“To take the poor chap’s cigarettes away from him,” he wrote, “would be rather like taking away [the] white stick from a blind man.”
If that particular explanation seems like a stretch, Fisher offered another. If smoking doesn’t cause cancer and cancer doesn’t cause smoking, then perhaps a third factor causes both. Genetics struck him as a possibility.
To make this case, Fisher gathered data on identical twins in Germany and showed that twin siblings were more likely to mimic one another’s smoking habits. Perhaps, Fisher speculated, certain people were genetically predisposed to crave of cigarettes.
Was there a similar familial pattern for lung cancer? Did these two predispositions come from the same hereditary trait? At the very least, researchers ought to look into this possibility before advising people to toss out their cigarettes.
And yet nobody was.
“Unfortunately, considerable propaganda is now being developed to convince the public that cigarette smoking is dangerous,” he wrote. “It is perhaps natural that efforts should be made to discredit evidence which suggests a different view.”
Though Fisher was in the minority, he was not alone in taking this “different view.” Joseph Berkson, the chief statistician at the Mayo Clinic throughout the 1940s and 50s, was also a prominent skeptic on the smoking-cancer question, as was Charles Cameron, president of the American Cancer Society. For a time, many of Fisher’s peers in academic statistics, including Jerzy Neyman, questioned the validity of a causal claim. But before long, the majority buckled under the weight of mounting evidence and overwhelming consensus.
But not Fisher. He died in 1962 (of cancer, though not of the lung). He never conceded the point.