Principles for Valid Histopathologic Scoring in Research

Histopathologic scoring is a tool by which semiquantitative data can be obtained from tissues. Initially, a thorough understanding of the experimental design, study objectives, and methods is required for the pathologist to appropriately examine tissues and develop lesion scoring approaches. Many principles go into the development of a scoring system such as tissue examination, lesion identification, scoring definitions, and consistency in interpretation. Masking (aka “blinding”) of the pathologist to experimental groups is often necessary to constrain bias, and multiple mechanisms are available. Development of a tissue scoring system requires appreciation of the attributes and limitations of the data (eg, nominal, ordinal, interval, and ratio data) to be evaluated. Incidence, ordinal, and rank methods of tissue scoring are demonstrated along with key principles for statistical analyses and reporting. Validation of a scoring system occurs through 2 principal measures: (1) validation of repeatability and (2) validation of tissue pathobiology. Understanding key principles of tissue scoring can help in the development and/or optimization of scoring systems so as to consistently yield meaningful and valid scoring data.

[1]  D. Meyerholz,et al.  Transepithelial migration of neutrophils into the lung requires TREM-1. , 2013, The Journal of clinical investigation.

[2]  F. Mutinelli,et al.  Expression of Ki67, BCL-2, and COX-2 in Canine Cutaneous Mast Cell Tumors , 2013, Veterinary pathology.

[3]  C. Sempoux,et al.  Novel Histologic Scoring System for Long‐Term Allograft Fibrosis After Liver Transplantation in Children , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  A. Vincent,et al.  Kinetics of Lung Lesion Development and Pro-Inflammatory Cytokine Response in Pigs With Vaccine-Associated Enhanced Respiratory Disease Induced by Challenge With Pandemic (2009) A/H1N1 Influenza Virus , 2012, Veterinary pathology.

[5]  K. Adachi,et al.  Spontaneous Glomerular and Tubulointerstitial Lesions in Common Marmosets (Callithrix jacchus) , 2012, Veterinary pathology.

[6]  D. Meyerholz,et al.  Genetically modified species in research: opportunities and challenges for the histology core laboratory , 2012, Journal of histotechnology.

[7]  M. Coëffier,et al.  Juvenile ferric iron prevents microbiota dysbiosis and colitis in adult rodents. , 2012, World journal of gastroenterology.

[8]  Takuji Tanaka,et al.  International Harmonization of Toxicologic Pathology Nomenclature , 2012, Toxicologic pathology.

[9]  S. Blad,et al.  Developmental Outcome at 6.5 Years After Acidosis in Term Newborns: A Population-Based Study , 2012, Pediatrics.

[10]  David K Meyerholz,et al.  Successful integration of the histology core laboratory in translational research , 2012, Journal of histotechnology.

[11]  C. Begley,et al.  Drug development: Raise standards for preclinical cancer research , 2012, Nature.

[12]  M. Borrelli,et al.  Correlation of MRI findings to histology of acetaminophen toxicity in the mouse. , 2012, Magnetic resonance imaging.

[13]  G. D. Johnson,et al.  A Forensic Investigation Into the Etiology of Bat Mortality at a Wind Farm: Barotrauma or Traumatic Injury? , 2012, Veterinary pathology.

[14]  Caroline J. Zeiss,et al.  Designing Phenotyping Studies for Genetically Engineered Mice , 2012, Veterinary pathology.

[15]  J. Ward,et al.  Pathobiology of Aging Mice and GEM , 2012, Veterinary pathology.

[16]  M. Rieder,et al.  Translational Research in Pediatrics: Tissue Sampling and Biobanking , 2012, Pediatrics.

[17]  R. Sellers The Gene or Not the Gene—That Is the Question , 2012, Veterinary pathology.

[18]  K. Pandher,et al.  Recommendations for the Evaluation of Pathology Data in Nonclinical Safety Biomarker Qualification Studies , 2011, Toxicologic pathology.

[19]  S. Shott Wrapping it all up. Statistics in veterinary medicine. Flowcharts. , 2011, Journal of the American Veterinary Medical Association.

[20]  F. Prinz,et al.  Believe it or not: how much can we rely on published data on potential drug targets? , 2011, Nature Reviews Drug Discovery.

[21]  Abbas Cheddad,et al.  An improved protocol for optical projection tomography imaging reveals lobular heterogeneities in pancreatic islet and β-cell mass distribution , 2011, Islets.

[22]  Jerrold M. Ward,et al.  Grading of Lesions , 2011, Toxicologic pathology.

[23]  Tom Holland,et al.  Analysis of Unbiased Histopathology Data from Rodent Toxicity Studies (or, Are These Groups Different Enough to Ascribe It to Treatment?) , 2011, Toxicologic pathology.

[24]  W. Bishai,et al.  A modified scoring system to describe gross pathology in the rabbit model of tuberculosis , 2011, BMC Microbiology.

[25]  R. Pearson,et al.  Histopathology grading systems for characterisation of human knee osteoarthritis--reproducibility, variability, reliability, correlation, and validity. , 2011, Osteoarthritis and cartilage.

[26]  S. Shott Detecting statistical errors in veterinary research. , 2011, Journal of the American Veterinary Medical Association.

[27]  J. Ward,et al.  Proliferative and Nonproliferative Lesions of the Rat and Mouse Hepatobiliary System , 2010, Toxicologic pathology.

[28]  A. Aderem,et al.  Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria , 2010, Nature Immunology.

[29]  C. Little,et al.  The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. , 2010, Osteoarthritis and cartilage.

[30]  C. Pannucci,et al.  Identifying and Avoiding Bias in Research , 2010, Plastic and reconstructive surgery.

[31]  K. Legge,et al.  Oseltamivir treatment prevents the increased influenza virus disease severity and lethality occurring in chronic ethanol consuming mice. , 2010, Alcoholism, clinical and experimental research.

[32]  M. Payton,et al.  Pulmonary Histopathology of Cytauxzoon felis Infections in the Cat , 2010, Veterinary pathology.

[33]  J. Dewulf,et al.  Control of Clostridium perfringens-induced necrotic enteritis in broilers by target-released butyric acid, fatty acids and essential oils , 2010, Avian pathology : journal of the W.V.P.A.

[34]  Hanlin L. Wang,et al.  Murine model of Hirschsprung-associated enterocolitis. I: phenotypic characterization with development of a histopathologic grading system. , 2010, Journal of pediatric surgery.

[35]  M. Prokop,et al.  Semiquantitative Assessment of Cardiovascular Disease Markers in Multislice Computed Tomography of the Chest: Interobserver and Intraobserver Agreements , 2010, Journal of computer assisted tomography.

[36]  M. Sutherland,et al.  Derivation and validation of murine histologic alterations resembling asthma, with two proposed histologic grade parameters , 2009, BMC Immunology.

[37]  S. Murthy,et al.  Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[38]  G. Kayser,et al.  Theory of sampling and its application in tissue based diagnosis , 2009, Diagnostic pathology.

[39]  A. Young,et al.  Synovial pathology in an ovine model of osteoarthritis: effect of intraarticular hyaluronan (Hyalgan). , 2008, Clinical and experimental rheumatology.

[40]  P. Treuting,et al.  Serum biomarkers in a mouse model of bacterial‐induced inflammatory bowel disease , 2008, Inflammatory bowel diseases.

[41]  H. Bolte,et al.  Standardized quantification of pulmonary fibrosis in histological samples. , 2008, BioTechniques.

[42]  M. Grafe,et al.  Long-term histological outcome after post-hypoxic treatment with 100% or 40% oxygen in a model of perinatal hypoxic–ischemic brain injury , 2008, International Journal of Developmental Neuroscience.

[43]  J. Dewulf,et al.  Quantification of gut lesions in a subclinical necrotic enteritis model , 2007, Avian pathology : journal of the W.V.P.A.

[44]  S. Krakowka,et al.  A reproducible scoring system for quantification of histologic lesions of inflammatory disease in mouse gastric epithelium. , 2007, Comparative medicine.

[45]  Karl P. Pfeiffer,et al.  Statistical errors in medical research--a review of common pitfalls. , 2007, Swiss medical weekly.

[46]  S. Marks,et al.  Prevalence and Histopathologic Characteristics of Pancreatitis in Cats , 2007, Veterinary pathology.

[47]  D. Ferriero,et al.  Acute Hypoxia-Ischemia Results in Hydrogen Peroxide Accumulation in Neonatal But Not Adult Mouse Brain , 2006, Pediatric Research.

[48]  Gregory T Sica,et al.  Bias in research studies. , 2006, Radiology.

[49]  S. Jimenez,et al.  Osteoarthritis cartilage histopathology: grading and staging. , 2006, Osteoarthritis and cartilage.

[50]  J. Crawford,et al.  Pathology as the enabler of human research , 2005, Laboratory Investigation.

[51]  Shayne C. Gad,et al.  Statistics and Experimental Design for Toxicologists and Pharmacologists , 2005 .

[52]  Tom Holland,et al.  The Comparative Power of the Discriminant Methods Used in Toxicological Pathology , 2005, Toxicologic pathology.

[53]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[54]  A. Viera,et al.  Understanding interobserver agreement: the kappa statistic. , 2005, Family medicine.

[55]  J. Sundberg,et al.  Refined histopathologic scoring system improves power todetect colitis QTL in mice , 2004, Mammalian Genome.

[56]  Adam R Ferguson,et al.  A simple post hoc transformation that improves the metric properties of the BBB scale for rats with moderate to severe spinal cord injury. , 2004, Journal of neurotrauma.

[57]  C. Portier,et al.  Extended histopathology in immunotoxicity testing: interlaboratory validation studies. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[58]  Dawn G Goodman,et al.  Best Practices Guideline: Toxicologic Histopathology , 2004, Toxicologic pathology.

[59]  B. Scallon,et al.  Validation of the interleukin‐10 knockout mouse model of colitis: antitumour necrosis factor‐antibodies suppress the progression of colitis , 2003, Clinical and experimental immunology.

[60]  D. Power,et al.  Interleukin‐10 inhibits experimental mesangial proliferative glomerulonephritis , 2002, Clinical and experimental immunology.

[61]  C. Okerberg,et al.  Qualitative and Quantitative Analysis of Nonneoplastic Lesions in Toxicology Studies , 2002, Toxicologic pathology.

[62]  C. A. Montgomery,et al.  Evaluating Mutant Mice: Anatomic Pathology , 2001, Veterinary pathology.

[63]  D. Altman,et al.  Blinding in clinical trials and other studies , 2000, BMJ : British Medical Journal.

[64]  A. Freemont,et al.  Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis , 1998, Gut.

[65]  S S Cross,et al.  Grading and scoring in histopathology , 1998, Histopathology.

[66]  S S Cross,et al.  Kappa statistics as indicators of quality assurance in histopathology and cytopathology. , 1996, Journal of clinical pathology.

[67]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[68]  T. Schoeb,et al.  Evaluation by Scoring and Computerized Morphometry of Lesions of Early Mycoplasma pulmonis Infection and Ammonia Exposure in F344/N Rats , 1986, Veterinary pathology.

[69]  James H. Torrie,et al.  Principles and procedures of statistics: a biometrical approach (2nd ed) , 1980 .

[70]  W. W. Daniel Applied Nonparametric Statistics , 1978 .

[71]  J. R. Landis,et al.  The measurement of observer agreement for categorical data. , 1977, Biometrics.

[72]  S S Stevens,et al.  On the Theory of Scales of Measurement. , 1946, Science.

[73]  C. G. Begley,et al.  Raise standards for preclinical cancer research , 2012 .

[74]  S. Shott Designing studies that answer questions. , 2011, Journal of the American Veterinary Medical Association.

[75]  A. Bendele,et al.  The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat. , 2010, Osteoarthritis and cartilage.

[76]  M. Festing Design and statistical methods in studies using animal models of development. , 2006, ILAR journal.

[77]  T. Bucci 8 – Basic Techniques , 2002 .

[78]  Douglas G Altman,et al.  Guidelines for the design and statistical analysis of experiments using laboratory animals. , 2002, ILAR journal.

[79]  W. Haschek,et al.  Handbook of toxicologic pathology , 1991 .

[80]  Joseph Chilver,et al.  The Basic Techniques , 1979 .