The introduction of randomized controlled experiments in agriculture in the 1920s and 1930s sometimes involved designing studies to make more than one comparison within the same experiment. Partly because of the different circumstances, such studies appear to have been rare in medicine at that time. An apparent early example of such a trial was reported by Wyckoff and his colleagues (1930), who evaluated the effects of digitalis in pneumonia on patients already allocated alternately to anti-pneumococcus serum. Factorial designs, simultaneously testing two or more treatments within the same investigation, can be a more economic form of research than organising several controlled trials to assess separately different treatments for the same condition. In the Wyckoff trial, however, no factorial analysis was envisaged or conducted. The design chosen was simply an efficient means for managing patients and trial procedures conveniently (see Doll 2003).
Infective hepatitis was one of the most common serious health problems within the armed forces operating in the Mediterranean at that time (Cohen 1944). There was interest in the potential of protein, and of sulphur-containing amino acids (such as methionine and cysteine) in particular, to alter the clinical course of ‘infective’ hepatitis in animals and possibly in humans (Beattie and Marshall 1944; Himsworth and Glynn 1944; Peters et al. 1944; Wilson et al. 1945), and there were varying opinions about the impact of dietary fat on recovery. The hepatitis/jaundice link with disturbed fat metabolism caused most clinicians to recommend low fat diets (although it would have been equally logical to increase fat content to compensate for its metabolic deficiencies).
In 1945, Wilson, Pollock and Harris (1945) had reported a controlled trial of the effects of supplementary methionine on hepatitis. As cysteine subsequently became more available from the wartime Ministry of Supply, they went on to assess the effects of dietary fat reduction as well as cysteine within a single, factorial trial reported in a paper that also served as a report to the Medical Research Council (Wilson et al. 1946).
Wilson, Pollock and Harris had formed four comparison groups from the start. They first allocated alternate patients to cysteine-supplemented and cysteine unsupplemented groups; then they allocated alternate patients within each of these two groups to high or low fat diets. There is no indication in the paper that the authors had considered that there might be an interaction between cysteine and dietary fat, another main reason for using factorial design trials, and so the results of dietary fat and cysteine supplementation were presented separately. In fact, the reason that fat reduction was evaluated as well as supplementation with cysteine appears to have been that it was difficult to maintain calorie input using low fat diets that were difficult to provide, unpalatable and probably unnecessary in patients who were often anorexic. These patients, whilst averse to greasy foods, were not so reluctant (in wartime-rationed Britain) to consume eggs, butter, cheese, milk and cream, which were rich in another sulphur-rich amino acid: methionine. It made sense to try to sort the matter out.
A modest benefit of cysteine as judged by numbers of relapses was suggested by the data; but the authors judged this to have reflected a higher number of relapses among controls, and “likely to have arisen merely by chance”. Their conclusions might have differed had they used more modern statistical techniques: the results actually indicate that chance alone was unlikely to have resulted in this difference in relapse rates (2/52 cases versus 10/51 controls, odds ratio 0.16, 95% confidence limits: 0.03, 0.79, generating a continuity-adjusted p value of 0.029). There was no hint, however, that dietary fat had any effect on cessation of relapses. This is probably just as well because the observation would have been confounded by a substantial difference between groups in the total calorific value of the diets (high fat: 3056 cals/day; low fat: 2025 cals/day), and possibly also with the dietary methionine differences, which were correlated with them. Dietary protein levels did not differ between groups.
The results should anyway be interpreted with caution because unconcealed sequential alternation would have increased the risk that the allocation schedule would not have been adhered to strictly, a danger that eventually led to the adoption of precautions to conceal allocation schedules the following year (MRC 1948; Chalmers 2010). Furthermore, in the hepatitis trial, patients in the different dietary fat groups were treated in separate wards housing both cysteine and control patients, an arrangement that researchers might try to avoid nowadays.
For both administrative ease and economic efficiency factorial trials became used to good effect to explore two or more treatments in a single experiment, including further study of the effects of treatments for hepatitis (Chalmers et al. 1955; Sackett 2008). Doll and Pygott (1952) used the factorial design to try to sort out the mess of multiple treatment options for patients with gastric ulcers (Doll 1964). Not only could they be used to study alternative therapies, but they were sometimes suitable (size and statistical power permitting) for investigating completely independent clinical problems (see, for example, Physicians Health Study Group 1989; Hennekens et al. 1996). It also became clear that factorial design trials constituted a powerful way of examining combination therapies and synergistic or antagonistic interactions between treatment combinations (ISIS-2 Collaborative Group 1988; MRC Vitamin Study Group 1991).
The complexities that factorial trials can create are not inconsiderable: assessing statistical power, especially if studying interactions; matching separate inclusion/exclusion criteria; dealing with separate side effects, compliance differences and cross-over problems; and coping with trial stopping decisions. However, all these issues were absent in the early example of a factorial trial reported by Wilson, Pollock and Harris. It was an affordable, sensible opportunity to examine two ‘separate’ clinical management issues in one series of patients. How ‘simple’ medical research once was……!
This James Lind Library article has been republished in the Journal of the Royal Society of Medicine 2018;111:424-425. Print PDF
References
Beattie J, Marshall J (1944). Methionine in the treatment of liver damage. Nature 153:525.
Cohen H (1944). Recent advances in medical treatment. Practitioner 153:193-205.
Chalmers I (2010). Why the 1948 MRC trial of streptomycin used treatment allocation based on random numbers. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/why-the-1948-mrc-trial-of-streptomycin-used-treatment-allocation-based-on-random-numbers/)
Chalmers TC, Eckhardt RD, Reynolds WE, Cigarroa JG, Deane N, Reifenstein RW, Smith CW, Davidson CS (1955). The treatment of acute infectious hepatitis. Controlled studies of the effects of diet, rest, and physical reconditioning on the acute course of the disease and on the incidence of relapses and residual abnormalities. Journal of Clinical Investigation 34: 1163-1235.
Doll R (1964). Medical treatment of gastric ulcers. Scottish Medical Journal 9:183-196.
Doll R (2003). Controlled trials testing two or more treatments simultaneously. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/controlled-trials-testing-two-or-more-treatments-simultaneously/)
Doll R, Pygott F (1952). Factors influencing the rate of healing of gastric ulcers: admission to hospital, phenobarbitone, and ascorbic acid. Lancet 1: 171-175.
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R (1996). Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine 334:1145-9.
Himsworth HP, Glynn LE (1944). Toxipathic and trophopathic hepatitis. Lancet 1:457-461.
ISIS-2 Collaborative Group (1988). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360.
Medical Research Council (1948b). Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation. BMJ 2:769-782.
MRC Vitamin Study Group (1991). Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131-137.
Peters RA, Thompson RHS, King AJ, Williams DI, Nicoll CS (1944). Sulphur-containing amino-acids and jaundice. Nature 153:773.
Physicians’ Health Study Research Group (1989). Final report on the aspirin component of the ongoing Physicians’ Health Study. New England Journal of Medicine 321:129-35.
Sackett DL (2008). A 1955 clinical trial report that changed my career. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/a-1955-clinical-trial-report-that-changed-my-career/)
Wilson C, Pollock MR, Harris AD (1945). Therapeutic trial of methionine in infective hepatitis. BMJ 1:399-401.
Wilson C, Pollock MR, Harris AD (1946). Diet in the treatment of infective hepatitis. Lancet 1:881-883.
Wyckoff J, Du Bois EF, Woodruff IO (1930). The therapeutic value of digitalis in pneumonia. JAMA 95:1243-1249.
Pollock JI (2017). A controlled trial using a factorial design reported in 1946.
© Jon Pollock, Faculty of Health and Social Care, University of the West of England, Bristol, Glenside Campus, Blackberry Hill, Stapleton, Bristol BS16 1DD. E-mail: jon.pollock@uwe.ac.uk
Cite as: Pollock JI (2017). A controlled trial using a factorial design reported in 1946. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/controlled-trial-using-factorial-design-reported-1946/)
The introduction of randomized controlled experiments in agriculture in the 1920s and 1930s sometimes involved designing studies to make more than one comparison within the same experiment. Partly because of the different circumstances, such studies appear to have been rare in medicine at that time. An apparent early example of such a trial was reported by Wyckoff and his colleagues (1930), who evaluated the effects of digitalis in pneumonia on patients already allocated alternately to anti-pneumococcus serum. Factorial designs, simultaneously testing two or more treatments within the same investigation, can be a more economic form of research than organising several controlled trials to assess separately different treatments for the same condition. In the Wyckoff trial, however, no factorial analysis was envisaged or conducted. The design chosen was simply an efficient means for managing patients and trial procedures conveniently (see Doll 2003).
Infective hepatitis was one of the most common serious health problems within the armed forces operating in the Mediterranean at that time (Cohen 1944). There was interest in the potential of protein, and of sulphur-containing amino acids (such as methionine and cysteine) in particular, to alter the clinical course of ‘infective’ hepatitis in animals and possibly in humans (Beattie and Marshall 1944; Himsworth and Glynn 1944; Peters et al. 1944; Wilson et al. 1945), and there were varying opinions about the impact of dietary fat on recovery. The hepatitis/jaundice link with disturbed fat metabolism caused most clinicians to recommend low fat diets (although it would have been equally logical to increase fat content to compensate for its metabolic deficiencies).
In 1945, Wilson, Pollock and Harris (1945) had reported a controlled trial of the effects of supplementary methionine on hepatitis. As cysteine subsequently became more available from the wartime Ministry of Supply, they went on to assess the effects of dietary fat reduction as well as cysteine within a single, factorial trial reported in a paper that also served as a report to the Medical Research Council (Wilson et al. 1946).
Wilson, Pollock and Harris had formed four comparison groups from the start. They first allocated alternate patients to cysteine-supplemented and cysteine unsupplemented groups; then they allocated alternate patients within each of these two groups to high or low fat diets. There is no indication in the paper that the authors had considered that there might be an interaction between cysteine and dietary fat, another main reason for using factorial design trials, and so the results of dietary fat and cysteine supplementation were presented separately. In fact, the reason that fat reduction was evaluated as well as supplementation with cysteine appears to have been that it was difficult to maintain calorie input using low fat diets that were difficult to provide, unpalatable and probably unnecessary in patients who were often anorexic. These patients, whilst averse to greasy foods, were not so reluctant (in wartime-rationed Britain) to consume eggs, butter, cheese, milk and cream, which were rich in another sulphur-rich amino acid: methionine. It made sense to try to sort the matter out.
A modest benefit of cysteine as judged by numbers of relapses was suggested by the data; but the authors judged this to have reflected a higher number of relapses among controls, and “likely to have arisen merely by chance”. Their conclusions might have differed had they used more modern statistical techniques: the results actually indicate that chance alone was unlikely to have resulted in this difference in relapse rates (2/52 cases versus 10/51 controls, odds ratio 0.16, 95% confidence limits: 0.03, 0.79, generating a continuity-adjusted p value of 0.029). There was no hint, however, that dietary fat had any effect on cessation of relapses. This is probably just as well because the observation would have been confounded by a substantial difference between groups in the total calorific value of the diets (high fat: 3056 cals/day; low fat: 2025 cals/day), and possibly also with the dietary methionine differences, which were correlated with them. Dietary protein levels did not differ between groups.
The results should anyway be interpreted with caution because unconcealed sequential alternation would have increased the risk that the allocation schedule would not have been adhered to strictly, a danger that eventually led to the adoption of precautions to conceal allocation schedules the following year (MRC 1948; Chalmers 2010). Furthermore, in the hepatitis trial, patients in the different dietary fat groups were treated in separate wards housing both cysteine and control patients, an arrangement that researchers might try to avoid nowadays.
For both administrative ease and economic efficiency factorial trials became used to good effect to explore two or more treatments in a single experiment, including further study of the effects of treatments for hepatitis (Chalmers et al. 1955; Sackett 2008). Doll and Pygott (1952) used the factorial design to try to sort out the mess of multiple treatment options for patients with gastric ulcers (Doll 1964). Not only could they be used to study alternative therapies, but they were sometimes suitable (size and statistical power permitting) for investigating completely independent clinical problems (see, for example, Physicians Health Study Group 1989; Hennekens et al. 1996). It also became clear that factorial design trials constituted a powerful way of examining combination therapies and synergistic or antagonistic interactions between treatment combinations (ISIS-2 Collaborative Group 1988; MRC Vitamin Study Group 1991).
The complexities that factorial trials can create are not inconsiderable: assessing statistical power, especially if studying interactions; matching separate inclusion/exclusion criteria; dealing with separate side effects, compliance differences and cross-over problems; and coping with trial stopping decisions. However, all these issues were absent in the early example of a factorial trial reported by Wilson, Pollock and Harris. It was an affordable, sensible opportunity to examine two ‘separate’ clinical management issues in one series of patients. How ‘simple’ medical research once was……!
This James Lind Library article has been republished in the Journal of the Royal Society of Medicine 2018;111:424-425. Print PDF
References
Beattie J, Marshall J (1944). Methionine in the treatment of liver damage. Nature 153:525.
Cohen H (1944). Recent advances in medical treatment. Practitioner 153:193-205.
Chalmers I (2010). Why the 1948 MRC trial of streptomycin used treatment allocation based on random numbers. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/why-the-1948-mrc-trial-of-streptomycin-used-treatment-allocation-based-on-random-numbers/)
Chalmers TC, Eckhardt RD, Reynolds WE, Cigarroa JG, Deane N, Reifenstein RW, Smith CW, Davidson CS (1955). The treatment of acute infectious hepatitis. Controlled studies of the effects of diet, rest, and physical reconditioning on the acute course of the disease and on the incidence of relapses and residual abnormalities. Journal of Clinical Investigation 34: 1163-1235.
Doll R (1964). Medical treatment of gastric ulcers. Scottish Medical Journal 9:183-196.
Doll R (2003). Controlled trials testing two or more treatments simultaneously. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/controlled-trials-testing-two-or-more-treatments-simultaneously/)
Doll R, Pygott F (1952). Factors influencing the rate of healing of gastric ulcers: admission to hospital, phenobarbitone, and ascorbic acid. Lancet 1: 171-175.
Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R (1996). Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. New England Journal of Medicine 334:1145-9.
Himsworth HP, Glynn LE (1944). Toxipathic and trophopathic hepatitis. Lancet 1:457-461.
ISIS-2 Collaborative Group (1988). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360.
Medical Research Council (1948b). Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation. BMJ 2:769-782.
MRC Vitamin Study Group (1991). Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338:131-137.
Peters RA, Thompson RHS, King AJ, Williams DI, Nicoll CS (1944). Sulphur-containing amino-acids and jaundice. Nature 153:773.
Physicians’ Health Study Research Group (1989). Final report on the aspirin component of the ongoing Physicians’ Health Study. New England Journal of Medicine 321:129-35.
Sackett DL (2008). A 1955 clinical trial report that changed my career. JLL Bulletin: Commentaries on the history of treatment evaluation (https://www.jameslindlibrary.org/articles/a-1955-clinical-trial-report-that-changed-my-career/)
Wilson C, Pollock MR, Harris AD (1945). Therapeutic trial of methionine in infective hepatitis. BMJ 1:399-401.
Wilson C, Pollock MR, Harris AD (1946). Diet in the treatment of infective hepatitis. Lancet 1:881-883.
Wyckoff J, Du Bois EF, Woodruff IO (1930). The therapeutic value of digitalis in pneumonia. JAMA 95:1243-1249.