Evaluating the effect of annotation size on measures of semantic similarity

Ontologies are widely used as metadata in biological and biomedical datasets. Measures of semantic similarity utilize ontologies to determine how similar two entities annotated with classes from ontologies are, and semantic similarity is increasingly applied in applications ranging from diagnosis of disease to investigation in gene networks and functions of gene products. Here, we analyze a large number of semantic similarity measures and the sensitivity of similarity values to the number of annotations of entities as well as to the difference in annotation size. We find that most similarity measures are sensitive to the number of annotations of entities as well as to the difference in annotation size; well-studied and richly annotated entities will usually show higher similarity than entities with only few annotations even in the absence of any biological relation. Our findings have significant impact on the interpretation of results that rely on measures of semantic similarity.