Natural experiments in medicine

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Sometimes experiments are so difficult to justify ethically by the evidence base that only governmental bodies, fringe and special interest anti-groups and the Press are likely do them. When one of these natural experiments occurs we can observe and learn from it. Sometimes a major advance in understanding occurs, more often the evidence base turns out to be right. This page is dedicated to those willing to learn from history.

Serendipity from coincidences between diseases and events is also worth noting. One of the early drugs tried against Tuberculosis was not very good, but patients in the arm of the trial receiving it were noted to be less miserable or depressed. It went into use as an early anti-depressant. An interesting substance with the potential to reduce blood pressure by its dilating effect on arteries was tried for this indication. It turned out to be disappointing, although it is now important in pulmonary hypertension but Sildenafil proved very useful for one of its unanticipated effects, and continues to be so.

  • In Boston around 1721 there was argument over variolation with churchmen on both sides "...within a year or two after the first experiment nearly three hundred persons had been inoculated by Boylston in Boston and neighbouring towns, and out of these only six had died; whereas, during the same period, out of nearly six thousand persons who had taken smallpox naturally, and had received only the usual medical treatment, nearly one thousand had died."[1]
Natural experiment around Boston
Total DiedMortality %
Variolated C 300 6C 2%
UnvariolatedC 6000C 1000C 14%*

gives it as about 14% rather than 17%, likely with closer figures.

Age specific mortality in males from ischaemic heart disease in Australia (blue) and USA (red) with introduction propranolol indicated respectively. The peak mortality occurred in 1965 in Australia and 1970 in the USA. Any possible correlation would be confounded by factors such as change in smoking habit and other drug introductions. In England and Wales male mortality from IHD, started falling consistently from 1965, a year after propranolol was first marketed. See (Report from Nat Statistical Office)
  • The US FDA delayed acceptance of the first beta-blocker, Propranolol, for a few years.
  • Toward the end of the 19th century in the USA smallpox outbreaks had become contained. Around that time anti-vaccinationists became more active, asserting the line of William Tebb that smallpox had diminished because of improved diet and health of the population, that the disease was less virulent and offered little risk to people who caught it young, and that vaccination in fact caused Smallpox. Vaccination fell into disuse. However, in the 1870s the disease became epidemic in what was now clearly a susceptible population. As states attempted to enforce existing vaccination laws or pass new ones, vigorous anti-vaccination movements arose. Nevertheless, vaccination increased, and yet again, Smallpox decreased and is now absent.
  • In the 1970's, the Sunday Times and various anti-vaccinationists managed to produce a fall in childhood immunisations. This was followed by an increase in the diseases[2], with accompanying deaths and injuries. And then repeated with the mixed Measles Mumps and Rubella immunisation.
  • In 1982 there was an epidemic of MPTP-induced parkinsonism in California repeating and confirming the 1976 case report suggesting that making a mistake in the synthesis of MPPP (1-Methyl-4-phenyl-4-piperidinol propionate), a synthetic opioid, produces MPTP which has been known since 1947 as a fairly selective neurotoxin to the substantia nigra. The neurotoxin theory of Parkinson's disease is offered as partial explanation for these and several other neurodegenerative condtions.
  • In New Zealand in 1996, fluvastatin became the reference price statin. This motivated patients to take the "free" drug, at inadequate doses, and a neat bit of epidemiology by Professor Jim Mann in Otago showed a not unexpected increase in vascular thrombotic events.[2].
  • In Nigeria, and therefore around Nigeria shortly afterward, in 2003, a political movement against polio vaccine greatly reduced its administration. Polio cases and the area they had been found in had been shrinking steadily, but now they began to expand.
  • In Japan, MMR vaccine was introduced in 1989, but the programme was terminated in 1993 and only single vaccines used thereafter Bandolier. "The incidence of all autistic spectrum disorders, and of autism, continued to rise after MMR vaccine was discontinued. The incidence of autism was higher in children born after 1992 who were not vaccinated with MMR than in children born before 1992 who were vaccinated. The incidence of autism associated with regression was the same during the use of MMR and after it was discontinued."[3] The conclusion reached by Bandolier on this elegant and well-observed natural experiment with 278 cases was that this destroys any possible causative link between use of the vaccine and autism. Whatever causes autism, it is not the MMR vaccine.[4]
Differental mortality for four year cohorts of acute myocardial infarction in New Jersey, showing deteriorating survival in the 1999-2002 cohort compared to the previous 8 years and differential survival for every 4 year period in favour of weekday admissions rather than weekend (prefix WE) admissions[3]
  • For religious, social and political reasons we have the concept of the working week and weekends. Cultures make varying provision for emergency health care at weekends but usually limit access to certain healthcare resources at weekends. This has been associated with differential mortality in patients with common medical illnesses depending upon what day they are admitted to hospital.[4][5][6][7] A common theme is that resources necessary to manage the patients are not available at weekends due to logistic reasons. With the ever more acutely orientated interventions to treat myocardial infarction this is not unexpectedly the case with this diagnosis. It has been estimated that 9 to 10 deaths per 1000 admissions could be saved by better acute service cover. However the data from this paper, while it shows ever increasing acute survival, also shows worsening long term survival.[8] An explanation for this is that many recently introduced interventions in acute myocardial infarction are based on short term studies and can have high take up because of the assumption that short term effectiveness translates into long term effectiveness. Modern acute interventions as practiced in the Eastern seaboard of the United States while reducing immediate mortality in myocardial infarction patients who make it to hospital could be increasing medium term mortality by up to 30 deaths per 1000 patients treated. The data is being watched very carefully.
  • Modernising Medical Careers. The UK big bang approach to major alterations to the training of doctors (future GPs as well as the hospital specialists it is ostensibly aimed at) qualifies as a natural experiment. The results will take some time to become clear, indeed the architects of it may discover those results at first hand if they suffer ill health after retirement.


  2. Begg E, Sidwell A, Gardiner S, Nicholls G, Scott R. The sorry saga of the statins in New Zealand--pharmacopolitics versus patient care. N Z Med J. 2003 Mar 14;116(1170) subscription needed to link
  3. Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE; Myocardial Infarction Data Acquisition System (MIDAS 10) Study Group. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med. 2007;356(11):1099-109.
  4. Bell CM, Redelmeier DA. Mortality among patients admitted to hospitals on weekends as compared with weekdays.N Engl J Med. 2001;345(9):663-8. Erratum in:N Engl J Med 2001;345(21):1580.
  5. Saposnik G, Baibergenova A, Bayer N, Hachinski V. Weekends: A Dangerous Time for Having a Stroke? Stroke. 2007 Mar 8;
  6. Barba R, Losa JE, Velasco M, Guijarro C, Garcia de Casasola G, Zapatero A. Mortality among adult patients admitted to the hospital on weekends. Eur J Intern Med. 2006 Aug;17(5):322-324.
  7. Foss NB, Kehlet H. Short-term mortality in hip fracture patients admitted during weekends and holidays. British journal of anaesthesia 2006;96:450-4. (Direct link – subscription may be required.)
  8. Kostis WJ, Demissie K, Marcella SW, Shao YH, Wilson AC, Moreyra AE; Myocardial Infarction Data Acquisition System (MIDAS 10) Study Group. Weekend versus weekday admission and mortality from myocardial infarction. N Engl J Med. 2007;356(11):1099-109.

See also

This article is a work in progress. Please feel free to contribute to it.

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