The problem of "protopathic bias" in case-control studies

Am J Med. 1980 Feb;68(2):255-8. doi: 10.1016/0002-9343(80)90363-0.


Among the many sources of bias that can affect the results of case-control research, protopathic bias occurs when a pharmaceutical agent is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected. In a case-control study of estrogens and endometrial cancer, approximately 10 per cent of the patients exposed to estrogens specifically stated that oral estrogens had been prescribed by their physician to treat an episode of uterine bleeding. This result was consistent with another study in which seven of 23 estrogen users were given the medication for the treatment of uterine bleeding before the diagnosis of cancer was made. Protopathic bias, which may account for much of the allegedly protective effect of oral contraceptives on the development of benign breast disease, can also occur in studies of aspirin and myocardial infarction, sex steroids and birth defects, and bronchodilators and death from asthma. This empiric demonstration of protopathic bias helps to indicate the need for careful precautions against its effects.

MeSH terms

  • Breast Diseases / prevention & control
  • Contraceptives, Oral / therapeutic use
  • Estrogens / adverse effects
  • Estrogens / therapeutic use*
  • Female
  • Humans
  • Research Design*
  • Retrospective Studies*
  • Risk
  • Time Factors
  • Uterine Hemorrhage / drug therapy*
  • Uterine Neoplasms / chemically induced*
  • Uterine Neoplasms / diagnosis


  • Contraceptives, Oral
  • Estrogens