An Alternative to the N.A.S. Biomarker Classification Scheme. L. Rhomberg, U.S. Environmental Protection Agency, 401 M St. SW (8602), Washington, DC 20460
The scheme proposed by the National Academy of Sciences for classifying biomarkers---distinguishing biomarkers of exposure, effect, and sensitivity---has gained great currency. While this classification has proved quite useful, it tends to confound distinctions based on (1) the intended use of the biomarker, (2) the nature of the biological measurement, and (3) the basis of inferences drawn from observation of the marker. This ambiguity is manifested in the almost inevitable question at the end of a biomarker talk: "Is this a marker of exposure or effect?" and the almost inevitable answer: "Well, both, in a way." This paper explores the reasons for such ambiguity and points out certain pitfalls in the frequent portrayal of biomarkers as intermediate points on a linear cascade of events from exposure to effect. An alternative scheme for classifying biomarkers is proposed (as a complement to the NAS scheme, rather than as a replacement) in which biomarkers are distinguished according to the cause-and-effect linkage they have with the "target" of inference (i.e., the property of the system one wishes to illuminate through use of the marker). One may either (1) infer an effect from observation of one of its causes, (2) infer a cause from observation of one of its effects, or (3) infer from one observed effect to another effect when they share a common cause. This approach stresses the nature of biomarkers as surrogate measures for cryptic or difficult-to-measure variables and asserts the primacy of explicitly establishing the biological reasoning behind any presumption that a biomarker can serve as a basis for quantitative inferences about unobserved quantities. [The views expressed in this paper are those of the author and do not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.]