The modern era of RCTs in medicine begins with Colebrook (1929), in which “drawing lots” was used to decide which kids would be irradiated (it’s not as bad as it sounds) – but if the parents refused consent then those children were added to the control group, which undoes much of the point of randomization but still [re]introduces the concept. The rigorous version appears two years later in Doull (1931), a study of the effect of ultra-violet light on the common cold. Doull worked at the Johns Hopkins School of Public Health and needed to figure out how to allocate his subjects into three groups in a manner that would allow for valid comparisons and analysis. According to Marks (2008), he consulted with a local biostatistician with a doctorate in mathematics, who suggested using colored dice to randomly allocate patients. Note the similar timing for these randomizations in clinical medicine as in agriculture (Eden and Fisher 1927).

The final piece of the medical puzzle falls into place with the famous streptomycin trial for tuberculosis (Medical Research Council 1948).<sup>15</sup> This is probably the most famous RCT in history, and many people have erroneously claimed that it was in fact the first RCT in history. The design was the brainchild of Austin Bradford Hill, whose degree was in economics (earned while recovering from tuberculosis himself) but who worked as a biostatistician and epidemiologist.<sup>16</sup> In addition to the important step of highlighting the need for randomization and of promoting it – he later wrote down influential formal criteria for imputing causality – Bradford Hill also promulgated another key aspect in the 1948 paper: the explicit idea of using randomization to consciously conceal foreknowledge, i.e. to “blind” the experimenter to treatment status whenever possible.

# <u>4. Psychology</u>

Human sensation, like psychical phenomena and mesmerism, was for most of history not considered a domain susceptible to quantitative scientific analysis. That began to change with the work of Gustav Fechner in the mid-19<sup>th</sup> century, who initiated the field of psychophysics (Fechner 1860) along with Ernst Weber. In particular, Fechner studied sensitivity of physical perception: e.g. how finely can a subject distinguish two masses, as a function of the base weight and the marginal difference between them? Although he deserves much credit for introducing concepts such as empirical experimentation and mathematical data analysis to this entire field, his methods were far from perfect. In particular, Fechner experimented on himself; for example in the perception experiments he knew all the relative weights in advance. He believed that he could consciously control for any resulting bias.

Müller (1879) took the next step, splitting the roles of subject and experimenter. He concurrently emphasized the notion of presenting stimuli in an irregular order ( _in buntem Wechsel_ ; see Dehue 1997), but neither he nor Fechner employed randomization – although Müller did eventually start to promote

> 15 The experiments for whooping-cough reported in Medical Research Council (1951), although published three years later, used an exactly analogous experimental approach and were actually begun several months earlier than those in the better-known streptomycin paper.

> 16 Bradford Hill later earned fame for his [non-randomized] work exhibiting a link between smoking and lung cancer; he was knighted in 1961.

9