Table 2

Example of the cause effect relationship with the human papillomavirus (HPV) and cervical cancer (adapted from Bosch et al27)

CriterionHPV-cervical cancer example
Sufficient strength of associationThe association between HPV DNA in cervical specimens and cervical cancer is one of the strongest ever observed for a human cancer. HPV-16 accounts for almost 50% of the types identified in cervical cancer. The cancer risk for any one of at least 10 HPV types or for any combination of HPV types does not differ significantly
Temporal relationship between exposure and outcomeHPV infections precede cervical precancerous lesions and cervical cancer by a substantial number of years. The epidemiology and the dynamics of HPV infection in populations satisfy previous observations that related cervical cancer to a sexually transmitted disease
Dose-response relationshipThe risk of cervical cancer may be related to estimates of viral load. The technology to estimate viral load is being developed and compliance with the biological gradient requirement needs to be further validated
ConsistencyThe association between HPV DNA in cervical specimens and cervical cancer is consistent in a large number of investigations in different countries and populations. There are no published studies with observations challenging the central hypothesis on causality
Biological plausibility and coherenceThe association of HPV DNA in cervical specimens and cervical cancer is plausible and coherent with previous knowledge. This includes in vitro experiments and observations in humans. Novel criteria of causality are being proposed and tested as molecular technology develops and is introduced into epidemiological research protocols
SpecificityThe association of type specific HPV DNA and cervical cancer is significantly different from random. Systematic patterns of HPV type and cervical cancer histology suggest a fair degree of specificity. Patterns are also observed when the scope of HPV and cancer expands to include the full spectrum of HPV types and the large number of additional cancer sites that have been investigated
AnalogyThe HPV and cervical cancer model is analogous to many other examples of papillomavirus induced papillomas and carcinomas and cancers caused by other viruses