Hypothesis / Commentary False Positives in Cancer Epidemiology

Background:A recent attempt to estimate the false-positive rate for cancer epidemiology studies is based on agents in International Agency for Research on Cancer (IARC) category 3 (agent not classifiable as to its carcinogenicity to humans) in the IARC Monographs Program. Methods: The estimation method is critiqued regarding biases caused by its reliance on the IARC classification criteria for assessing carcinogenic potential. Results: The privileged position given to epidemiologic studies by the IARC criteria ensures that the percentage of positive epidemiologic studies for an agent will depend strongly on the IARC category to which the agent is assigned. Because IARC category 3 is composed of agents with the lowest-assessed carcinogenic potential to which the estimation approach in question could be applied, a spuriously low estimated falsepositive rate was necessarily the outcome of this approach. Conclusions: Tendentious estimation approaches like that employed will by necessity produce spuriously low and misleading false positive rates. Impact:The recently reported estimates of the false-positive rate in cancer epidemiology are seriously biased and contribute nothing substantive to the literature on the very real problems related to false-positive findings in epidemiology. Cancer Epidemiol Biomarkers Prev; 22(1); 11–15. 2012 AACR. A recent article (1) attempted to estimate the falsepositive rate for cancer epidemiology studies based on agents in International Agency for Research on Cancer (IARC) category 3 (agent not classifiable as to its carcinogenicity to humans) in the IARC Monographs Program. The estimationmethodusedwasbasedon the assumption that the IARC classification of agents about their carcinogenic potential (or any similar human endeavor at reaching consensus) provides a scientifically sound basis for assessing the false-positive rate in cancer epidemiology studies. Any such consensus effort uses classification criteria, and we critique the proposed false-positive rate estimationmethod because of potential biases induced by its reliance on the IARC criteria for assessing carcinogenic potential. The IARC criteria give epidemiologic studies epistemic priority in working group deliberations, and accordingly, the IARC category to which an agent is assigned will depend strongly on the percentage of positive epidemiologic studies for that agent. Because IARC category 3 is composed of agents with inadequate evidence of cancer risk from epidemiologic studies, we argue that the reported false-positive rate estimates based on this IARC category seriously underestimate the actual false-positive rate in cancer epidemiology investigations. The false-positive rate was estimated as the percentage of positive studies among all epidemiologic studies assessing cancer risk for agents classified in IARC category 3, the IARC category corresponding to the lowest-assessed carcinogenic potential to which the proposed method could be applied (1). For an agent to be assigned to category 3, there must be inadequate evidence of carcinogenicity in both humans and animals. Because IARC gives the greatest probative weight to epidemiologic evidence, any agents, including noncarcinogens, with multiple-positive epidemiology studies would by IARC definitional criteria almost always be assigned to an IARC category indicative of a higher assessment of carcinogenic potential than that of category 3. An agentwith even a few positive epidemiologic findings will likely be assigned to category 2b (possibly carcinogenic to humans), category 2a (probably carcinogenic to humans), or sometimes category 1 (carcinogenic to humans). By the IARC classification criteria, agents in category 3 will have almost no positive epidemiology studies, and thus the evaluation by the authors of the percentage of positive epidemiologic studies for category 3 agents was guaranteed in advance to provide a misleadingly low estimate of the false-positive rate. The fundamentally flawed nature of the estimation method used in the article (1) is best understood by considering the approach its authors indicate that they would have preferred to use to estimate the false-positive rate. They indicate that ideally theywould have estimated Authors' Affiliation: International Epidemiology Institute, Rockville, Maryland Corresponding Author: Joseph K. McLaughlin, International Epidemiology Institute, 1455 Research Boulevard, Suite 550, Rockville, MD 20850. Phone: 301-424-1054; Fax: 301-424-1053; E-mail: jkm@iei.us doi: 10.1158/1055-9965.EPI-12-0995 2012 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention www.aacrjournals.org 11 American Association for Cancer Research Copyright © 2013 on January 4, 2013 cebp.aacrjournals.org Downloaded from Published OnlineFirst November 1, 2012; DOI:10.1158/1055-9965.EPI-12-0995