Silicosis, Lung Cancer, and Evidence-Based Medicine in North America

According to her biographies[1], Madge Thurlow Macklin excelled in mathematics, graduated from Goucher College, received a fellowship to study physiology at Johns Hopkins University, and then went on graduate with honors from the Johns Hopkins Medical School, in 1919.  Along the way, she acquired a husband, Charles C. Macklin, an associate professor of anatomy at Hopkins, and had her first child.

In 1921, the Macklins moved to London, Ontario, to take positions at the University of Western Ontario.  Charles received an appointment as a professor of histology and embryology, and went on to distinguish himself in pulmonary pathology. Madge Macklin received an appointment as a part-time instructor at Western, but faced decades of resistance because of her sex and her marriage to a professor. She was never promoted beyond part-time assistant professor, at Western.

Despite the hostile work environment, Madge Macklin published and lectured on statistical and medical genetics.  Her papers made substantial contributions to the inheritable aspects of human cancer and other diseases.

Macklin advocated tirelessly for the inclusion of medical genetics in the American medical school curriculum. See, e.g., Marge T. Macklin, “Should The Teaching Of Genetics As Applied To Medicine Have A Place In The Medical Curriculum?” 7 J. Ass’n Am. Med. Coll. 368 (1932); “The Teaching of Inheritance of Disease to Medical Students: A Proposed Course in Medical Genetics,” 6 Ann. Intern. Med. 1335 (1933). Her advocacy largely succeeded both in medical education and in the recognition of the importance of genetics for human diseases.

Macklin’s commitment to medical genetics led her to believe that physicians had a social responsibility to engage in sensible genetics counseling, and reasonable guidance on procreation and birth control. In 1930, Macklin helped found the Eugenics Society of Canada, and went on to serve as its Director in 1935. Her writings show none of the grandiosity or pretensions that lie in creating a master race, as much as avoiding procreation among imbeciles. See, e.g., Madge Macklin, “Genetical Aspects of Sterilization of the Mentally Unfit,” 30 Can. Med. Ass’n J. 190 (1934).

Some of her biographers suggest that Macklin lost her position at Western due to her views on eugenics, and others suggest that her trenchant criticisms of the inequity of the University’s sexism led her to go to Ohio State University in 1946, as a cancer researcher, funded by the National Research Council. Macklin taught genetics at Ohio State, something that Western never permitted her to do. In 1959, three years before her death, Macklin was elected president of the American Society for Human Genetics.

By all accounts, Macklin was an extraordinary woman and a gifted scientist, but my interest in her work stems from her recognition in the 1930s and 1940s, for the need for greater rigor in drawing etiological inferences in medical science.  Well ahead of her North American colleagues, Macklin emphasized the need to rule out bias, confounding, and chance before accepting apparent associations as causal. She wrote with unusual clarity and strength on the subject, decades before Sir Austin Bradford Hill. Her early mathematical prowess served her well in rebutting case reports and associations that were often embraced uncritically.

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In 1939, Professor Max Klotz of the University of Toronto, reported a very crude analysis from which he inferred a putative association between silicosis and lung cancer. Max O. Klotz, “The Association of Silicosis and Carcinoma of the Lung, 35 Am. J. Cancer 38 (1939). Klotz was a pathologist, and he worked with autopsy series, without statistical tools or understanding, as was common at the time. Macklin wrote a thorough refutation, which amply illustrates her abilities and her clear thinking:

“Another type of improper control for analysing cancer data arises through ignoring the fact that every cancer has a specific age incidence, and sex predilection. I have already mentioned breast, uterine and prostatic cancers, but other types of cancer, not of the generative organs,  have marked sex predilection. Cancer of the lung is a good example. It occurs four times as frequently in the male as in the female. If we desire to make any study of causative factors in lung cancer we must be sure that our control group is comparable to our experimental group. Again I will take an example from the literature. A worker was investigating the possible role of silicosis in inducing lung cancer. He compared the incidence of lung cancer in a group of 50 cases of silicosis, and in a large necropsy group of 4500 ‘unselected’ cases from a general hospital. He found that lung cancer was 7 times as frequent in the silicosis group as in the unselected necropsies. This is an excellent example of misunderstanding as to what is meant by ‘random’ sample. Because the 4500 necropsies were ‘unselected’ the worker thought that he had a good control group. As a matter of fact, in order to have a good control, he needed to select very carefully from these 4500 necropsies, those which he was to use as his standard. He forgot two things:

(1) that lung cancer is 4 times as common in the male as in the female and that all his silicosis cases were males, therefore his unselected necropsies should have been highly selected to contain only males. Assuming that half of his 4500 necropsies were females, and that among them one fifth of the lung cancers occurred, one can easily show that had his control group been all males as was his silicosis group, lung cancer would have been only 4.8 times as common among the silicosis patients as among the general necropsy group instead of 7 times as he found it.

(2) The second thing he forgot is that silicosis does not develop until 15 or 20 years of exposure have passed by. That placed all his silicosis patients in the late forties or early fifties, just when lung cancer becomes most common. Many of his general necropsy group were in the age range below 45, hence not in the lung cancer age. He should have selected only those males from the necropsy group who matched the age distribution of his silicosis patients. If he then found a significantly higher percentage of lung cancer among his silicosis patients he could have suggested a relationship between the two. Until that control group is properly studied, his results are valueless.”



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“The second point to be noted is that the control group should correspond as nearly as possible in all respects with the group under investigation, with the single exception of the etiologic factor being investigated. If silicosis is being considered as a causative agent in lung cancer, the control group should be as nearly like the experimental or observed group as possible in sex, age distribution, race, facilities for diagnosis, other possible carcinogenic factors, etc. The only point in which the control group should differ in an ideal study would be that they were not exposed to free silica, whereas the experimental group was. The incidence of lung cancer could then be compared in the two groups of patients.

This necessity is often ignored; and a ‘random’ control group is obtained for comparison on the assumption that any group taken at random is a good group for comparison. Fallacious results based on such studies are discussed briefly.”

Madge Thurlow Macklin, “Pitfalls in Dealing with Cancer Statistics, Especially as Related to Cancer of the Lung,” 14 Diseases Chest 525 532-33, 529-30 (1948).

The recognition that uncontrolled, or improperly controlled, research was worthless was a great advance in thinking about medical causation.  In the 1940s, Macklin was ahead of her time; indeed, if she were alive today, she would be ahead of many contemporary epidemiologists.


[1]Barry Mehler, “Madge Thurlow Macklin,” from Barbara Sicherman and Carl Hurd Green, eds., Notable American Women: The Modern Period 451-52 (1980); Laura Lynn Windsor, Women in Medicine: An Encyclopedia 134 (2002).







[1] Barry Mehler, “Madge Thurlow Macklin,” from Barbara Sicherman and Carl Hurd Green, eds., Notable American Women: The Modern Period 451-52 (1980); Laura Lynn Windsor, Women in Medicine: An Encyclopedia 134 (2002).


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