A conceptual framework for the validation and use of biologic markers

Schulte, Paul A.

doi:10.1016/s0013-9351(89)80029-5

Cited by 80 publications

(33 citation statements)

References 18 publications

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“…As shown in Figure 3, (59). As shown in Figure 4 (58,59,61), the biomarker scheme is essentially the same as that used for the exposure-dose-response continuum. Thus, biomarker data based in a mode-of-action framework can essentially provide precursor lesion data and can serve as a basis for a parallelogram approach for extrapolation and determination of human homology for the health effect of interest, as shown in Figure 5 (59).…”

Section: Laboratory Animal Data As a Predictor Of Human Responsementioning

confidence: 99%

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Dietert

Etzel

Chen

et al. 2000

Environ Health Perspect

227

122

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Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

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Section: Laboratory Animal Data As a Predictor Of Human Responsementioning

confidence: 99%

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Dietert

Etzel

Chen

et al. 2000

Environ Health Perspect

227

122

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“…These characteristics have been widely discussed (1,(6)(7)(8)(9) (15) have shown that slow acetylators develop more 4-aminobiphenyl-hemoglobin adducts than fast acetylators. Whether the acetylation phenotype is a risk factor for cancer has not been corroborated, despite widely cited references (16,17) to a higher frequency of slow acetylators among bladder cancer cases.…”

Section: Conceptual and Methodologic Issuesmentioning

confidence: 99%

Biomarkers in epidemiology: scientific issues and ethical implications.

Schulte

1992

Environ Health Perspect

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The current generation of biologic markers have three characteristics that differentiate them from previous ones. These include the ability to detect xenobiotics at concentrations at the cellular and molecular level, to detect earlier biologic changes presumptive of disease or disease risk, and to identify a detailed continuum of events between an exposure and resultant disease. If biomarkers are to enhance cancer epidemiology, they must be valid, reliable, and practical. When these characteristics have not been previously demonstrated, pilot studies should be conducted prior to the primary study. Interdisciplinary communication and collaboration is required so that useful markers are selected and that collection and handling, assay, and interpretation are appropriate. The status of many biomarkers is that they have been developed in the laboratory but lack validation for field use. Validation of a marker for use in a population requires attention to issues of background prevalence, sample size, natural history, persistence, variability, confounding factors, and predictive value. Additionally, practical features such as subject preparation, access to specimens, specimen storage aspects, and costs must be clarified. Ultimately, the use of biologic markers in epidemiologic studies will depend on how well the markers increase ability to reduce misclassification, provide for better interpretation of exposure-disease associations, and increase opportunities for prevention. Validation studies and general research using biomarkers also have clinical, ethical, and legal implications. These range from communicating uncertainty about the meaning of a marker to the kinds of societal response that result when groups or individuals are identified as having an "abnormal" marker frequency. Conceptual and Methodologic IssuesThe scientific literature on biomarkers has been characterized more by attention to issues surrounding the development of assays than by the methodology for their use in epidemiologic research or by their ethical and legal impact. Such emphasis on the analytical is natural in view of the stage of development of markers; however, if markers are to be useful in cancer epidemiology and in human risk assessment, issues related to epidemiological and field studies must be addressed. To be useful in cancer epidemiology, applications of biomarkers should reduce misclassification of exposures and disease, enhance detection of exposure-disease associations, or increase opportunities for intervention. Biomarkers have two particularly useful characteristics: analytical sensitivity and the ability to represent steps in a heuristic continuum between

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“…The objective ofthis paper is to identify and explore the range ofthe concept ofvalidity and to address how considerations that comprise the concept ofvalidity and to address how validity pertains to the use of biological markers in quantitative risk assessment. The term "biological marker" has been defined as an indicator that signals events in biological systems or samples, and it is generally taken to be any biochemical, genetic, or immunologic indicator that can be measured in a biological specimen (4)(5)(6)(7). Ascribed to the term biological marker is its role as an indicator ofevents in a continuum between exposure to a xenobiotic substance and resultant disease (4,6).…”

Section: Introductionmentioning

confidence: 99%

“…The term "biological marker" has been defined as an indicator that signals events in biological systems or samples, and it is generally taken to be any biochemical, genetic, or immunologic indicator that can be measured in a biological specimen (4)(5)(6)(7). Ascribed to the term biological marker is its role as an indicator ofevents in a continuum between exposure to a xenobiotic substance and resultant disease (4,6). Biologic markers can refer to any ofthree categories of events: exposure, effect, and susceptibility.…”

Section: Introductionmentioning

confidence: 99%

Validation of Biological Markers for Quantitative Risk Assessment

Schulte¹,

Mazzuckelli²

1991

Environmental Health Perspectives

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The evaluation of iolgia markers is recoied as necsry to the future oftokcOy , epideniology, and q Iive risk assment. For bio cl nmrkes to becm widely accepted, their validity must be ascertained. This paper explores the range ofconsiderations that compose the concept of validiBt as it applies to the evaluation of bioogical markers. Three broad categories of validity (meaem ent, internal study, and external) are discussed in the context of evWaluating data for use inquantitative risk at. Frticular attention is given to the importnce ofmeuement validity in the consideration ofwhether to use biological markers in epidemiologic studies. The Three broad categories of validity can be distinguished: measurement validity, internal study validity, and external validity. Measurement validity has been defined as an expression ofthe degree to which ".. . a measurement measures what it purports to measure" (9). Internal study validity is the degree to which inferences drawn from a sample are warranted when account is taken of the study methods, the representativeness of the study sample, and the nature ofthe population from which the sample is drawn (9). External study validity is the extent to which the findings of a study can be generalized to other populations (9). likely that the risk assessments constructed from those measurements will also be invalid. Measurement validity characterizes the extent to which a marker ofa phenomenon has content validity (i.e., pertains to the underlying phenomenon); construct validity (i.e., correlates with other relevant characteristics of the underlying phenomenon); and criterion validity (i.e., predicts some component of the underlying phenomenon). In general, these three components ofmeasurement validity are best assessed in terms of the extent or degree to which they apply to the underlying phenomenon, rather than as an all-or-none condition (JO). Content ValidityContent validity is the extent to which a marker "incorporates the domain ofthe phenomenon under study" (9). For example, a marker of internal dose will have content validity if it reflects the dose contributed by all routes of exposure. A marker of effect will have content validity if it encompasses the essential characteristics of the disease it represents. In other words, the marker must pertain to the appropriate target organ, or its relationship to the natural history ofthe disease in question must be unambiguous. For example, a DNA adduct of benzo(a)pyrene (BaP) will have content validity as a marker of exposure in a study ofBaP-induced lung cancer, since the involvement ofDNA in BaP-induced carcinogenesis is well documented. In contrast, the development of DNA adducts in the N7 position might not have content validity as a marker of biologically effective dose ifthe 06 methylguanine adduct is shown to be that which is most clearly related to the carcnogenic process. However, the N7 adducts might be reasonably valid markers ofBaP biologically effective dose ifthe production of06 and N7 adducts are directly proportion...

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A conceptual framework for the validation and use of biologic markers

Cited by 80 publications

References 18 publications

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Biomarkers in epidemiology: scientific issues and ethical implications.

Validation of Biological Markers for Quantitative Risk Assessment

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