A Glasgow University academic has argued that Sir Arthur Conan Doyle, who trained as a doctor before becoming famous for his Sherlock Holmes stories, may have anticipated two major medical discoveries in his 1890 novel The Sign of Four. Professor Mike Barrett suggests the book hints at malaria's transmission by mosquitoes years before this was scientifically proven, and appears to describe the tropical disease kala-azar over a decade before it was formally identified, reflecting Conan Doyle's genuine interest in infectious and tropical diseases from his medical career.

Barrett's research centres on the character Major John Sholto, whose mysterious illness and death in the novel he believes may be an early literary depiction of kala-azar (also known as visceral leishmaniasis or black fever), a disease not officially identified until 1903 by Sir William Boog Leishman. The novel also links mosquitoes, swamps and fever in ways that appear to echo emerging theories about malaria transmission championed by Sir Patrick Manson, a link definitively proven only in 1897 by Sir Ronald Ross. Sholto's symptoms, including an enlarged spleen and a bedside bottle of quinine, suggest Conan Doyle was drawing on contemporary medical thinking, though the author never explicitly names the disease that kills the character.