02484nas a2200337   4500000000100000008004100001260001500042653001600057653002100073653001900094653002400113653002500137653001500162653001800177100002300195700002400218700001800242700002000260700002100280700002200301700002000323700001700343700002500360700001900385245011700404856007200521300001100593490000800604520152000612022001402132       2023                            d  c2023-02-0110aConcordance10aDrug development10aHistopathology10apreclinical studies10aStatistical modeling10aToxicology10aTranslational1 aPeter S. R. Wright1 aKatharine A. Briggs1 aRobert Thomas1 aGraham F. Smith1 aGareth Maglennon1 aPaulius Mikulskis1 aMelissa Chapman1 aNigel Greene1 aBenjamin U. Phillips1 aAndreas Bender00aStatistical analysis of preclinical inter-species concordance of histopathological findings in the eTOX database  uhttps://www.sciencedirect.com/science/article/pii/S0273230022001957  a1053080 v1383 aPreclinical inter-species concordance can increase the predictivity of observations to the clinic, potentially reducing drug attrition caused by unforeseen adverse events. We quantified inter-species concordance of histopathological findings and target organ toxicities across four preclinical species in the eTOX database using likelihood ratios (LRs). This was done whilst only comparing findings between studies with similar compound exposure (Δ|Cmax| ≤ 1 log-unit), repeat-dosing duration, and animals of the same sex. We discovered 24 previously unreported significant inter-species associations between histopathological findings encoded by the HPATH ontology. More associations with strong positive concordance (33% LR+ > 10) relative to strong negative concordance (12.5% LR- < 0.1) were identified. Of the top 10 most positively concordant associations, 60% were computed between different histopathological findings indicating potential differences in inter-species pathogenesis. We also observed low inter-species target organ toxicity concordance. For example, liver toxicity concordance in short-term studies between female rats and dogs observed an average LR+ of 1.84, and an average LR- of 0.73. This was corroborated by similarly low concordance between rodents and non-rodents for 75 candidate drugs in AstraZeneca. This work provides new statistically significant associations between preclinical species, but finds that concordance is rare, particularly between the absence of findings.  a0273-2300