De-risking mechanistic claims through human-relevant validation of CVD disease models

DISEASE-11 proposals are assessed primarily on Excellence, with reviewers explicitly examining whether mechanistic insights are genuinely human-relevant and whether disease models adequately represent the biology underlying the claimed mechanisms. A frequent reason for score reduction is insufficient justification that observed mechanisms in models reflect human cardiovascular disease rather than model-specific artefacts. We contribute a platform that enables systematic, mechanistic validation of disease models against human CVD biology. Our approach compares animal models and NAMs to human molecular and pathway-level data in a context-specific manner, allowing consortia to demonstrate explicitly: which human disease mechanisms are captured by the selected models, which mechanisms are missing or distorted, and how these limitations affect interpretation of mechanistic results. Within a DISEASE-11 consortium, we directly support: Stronger Excellence scores, by substantiating mechanistic claims with evidence of human relevance Transparent discussion of model limitations, which reviewers increasingly expect rather than penalize Improved credibility of disease hypotheses by linking experimental results to human molecular pathology A clearer, defensible narrative explaining why the chosen models are appropriate for the specific scientific questions Our contribution reduces the risk of reviewer skepticism around mechanistic validity and helps ensure that disease-mechanism claims are perceived as robust, human-grounded and fundable.