How Valuable is Blind Evaluation in Histopathologic Examinations in Conjunction with Animal Toxicity Studies?

Weinberger, Morris A.

doi:10.1177/019262337900700204

Cited by 21 publications

(21 citation statements)

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“…Informed analysis is the standard practice for the NTP, as well as the toxicologic pathology industry as a whole, and is in accordance with the recommendations of the Society of Toxicologic Pathology and the American College of Veterinary Pathologists. 5 –10 The NTP’s peer review process provides a thorough review of the pathology data by highly trained pathologists using consistent terminology and criteria, and the final diagnoses in NTP studies represent a consensus between multiple, independent pathologists, providing the highest confidence in the NTP’s histopathology data and pathology review process. There is no evidence that the current approaches of informed histopathological evaluation in NTP studies have missed identifying potential hazards of significant public health concern.…”

Section: National Toxicology Program Position On Informed Analysis Fomentioning

confidence: 99%

National Toxicology Program Position Statement on Informed (“Nonblinded”) Analysis in Toxicologic Pathology Evaluation

et al. 2019

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The National Toxicology Program (NTP) uses histopathological evaluation of animal tissues as a key element in its toxicity and carcinogenicity studies. The initial histopathological evaluations are subjected to a rigorous peer review process involving several steps. The NTP peer review process is conducted by multiple, highly trained, and experienced toxicological pathologists employing standardized terminology. In addition, ancillary data, such as body and organ weights and clinical pathology findings, are used to corroborate the diagnoses. The NTP does employ masked analysis to confirm subtle lesions or severity scores, as needed, and during its Pathology Working Groups. The use of masked analysis can have a negative effect on histopathological evaluation because it is important for the pathologist to compare treated groups to the concurrent controls, which would not be possible in a blinded evaluation. Therefore, the NTP supports an informed approach to histopathological evaluation in its toxicity and carcinogenicity studies.

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Section: National Toxicology Program Position On Informed Analysis Fomentioning

confidence: 99%

National Toxicology Program Position Statement on Informed (“Nonblinded”) Analysis in Toxicologic Pathology Evaluation

et al. 2019

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“…Additional factors that may alter histopathologic evaluations, include the rater's inherent skill, education, training, experience, and mental noise, as well as diurnal fluctuations in mood, nutritional state, and energy. 32 The validity of a grading scheme is ultimately assessed by its repeatability between replicate measurements wherein a kappa value between -1 and þ1 is calculated from intra-and interobserver agreement of nonparametric ordinal measurements. 8,12,24 Kappa values of -1 and þ1 correspond to perfect disagreement and perfect agreement, respectively, while 0 corresponds to no relationship between the raters such that any consensus is due to chance.…”

Section: Creating Adapting and Applying A Grading/scoring Systemmentioning

confidence: 99%

“…25 Digital scanning of all slides in a study should be performed with the same objective, typically either 20Â or 40Â, to ensure consistent resolution per pixel. 32 Excessive mounting media, haphazardly placed coverslips, and thick paraffin sections will dictate the assignment of manual focus points instead of autofocusing methods. While brightfield slide scanning is approaching routine, oil immersion lenses require Z-stacking to view the same area at different fields of focus, and fluorescent scanners essentially require separate scans for each fluorophore.…”

Section: Creating Adapting and Applying A Grading/scoring Systemmentioning

confidence: 99%

Comparative Pathologists: Ultimate Control Freaks Seeking Validation!

Perle

2018

Vet Pathol

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Definable, reproducible, and meaningful are elemental features of grading/scoring systems, while thoroughness, accuracy, and consistency are quality indicators of pathology reports. The expertise of pathologists is significantly underutilized when it is limited to rendering diagnoses. The opportunity to provide guidance on animal model development, experimental design, optimal sample collection, and data interpretation not only contributes to job satisfaction but also, more importantly, promotes validation of the pathology data. Keys to validation include standard operating procedures, experimental controls, and standardized nomenclature applied throughout the experimental design and execution, tissue sampling, and slide preparation, as well as the creation or adaptation and application of semiquantitative grading/scoring systems. Diagnostic drift, thresholds, mental noise, and various diurnal fluctuations strongly influence the repeatability of grading/scoring systems used by the same or different pathologists. Quantitative image analyses are not plagued by the visual and cognitive traps that affect manual semiquantitative grading schemes but may still be affected by technical variables associated with necropsy, tissue sampling, and slide preparation. The validity of a grading scheme is ultimately assessed by its repeatability and biologic relevance, so it is important to correlate scores with comprehensive pathobiology data such as results of antemortem imaging, clinical pathology data, body and organ weights, and histopathologic evaluation of full tissue sets.

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“…On the other hand, most pathologists feel that the disadvantages of "blind" pathology outweigh the advantages (19). They assert that control animals must be examined first to determine the naturally occurring incidence and severity of neoplastic and nonneoplastic lesions.…”

Section: Confounding Factorsmentioning

confidence: 99%

Statistical Issues in the Design, Analysis and Interpretation of Animal Carcinogenicity Studies

Haseman¹

1984

Environmental Health Perspectives

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JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives.Statistical issues in the design, analysis and interpretation of animal carcinogenicity studies are discussed. In the area of experimental design, issues that must be considered include randomization of animals, sample size considerations, dose selection and allocation of animals to experimental groups, and control of potentially confounding factors.In the analysis of tumor incidence data, survival differences among groups should be taken into account. It is important to try to distinguish between tumors that contribute to the death of the animal and "incidental" tumors discovered at autopsy in an animal dying of an unrelated cause. Life table analyses (appropriate for lethal tumors) and incidental tumor tests (appropriate for nonfatal tumors) are described, and the utilization of these procedures by the National Toxicology Program is discussed. Despite the fact that past interpretations of carcinogenicity data have tended to focus on pairwise comparisons in generaland high-dose effects in particular, the importance of trend tests should not be overlooked, since these procedures are more sensitive than pairwise comparisons to the detection of carcinogenic effects.No rigid statistical "decision rule" should be employed in the interpretation of carcinogenicity data. Although the statistical significance of an observed tumor increase is perhaps the single most important piece of evidence used in the evaluation proeess, a number of biological factors must also be taken into account. The use of historical control data, the false-positive issue and the interpretation of negative trends are also discussed.

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How Valuable is Blind Evaluation in Histopathologic Examinations in Conjunction with Animal Toxicity Studies?

Cited by 21 publications

References 0 publications

National Toxicology Program Position Statement on Informed (“Nonblinded”) Analysis in Toxicologic Pathology Evaluation

National Toxicology Program Position Statement on Informed (“Nonblinded”) Analysis in Toxicologic Pathology Evaluation

Comparative Pathologists: Ultimate Control Freaks Seeking Validation!

Statistical Issues in the Design, Analysis and Interpretation of Animal Carcinogenicity Studies

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