Comparisons were performed based on ChemOnt 28 chemical class hierarchies to investigate prediction accuracy amongst structurally-related groups (Figure ). At the superclass level, only the benzenoids and organoheterocyclic compounds have a median spectral cosine score greater than 500 and an interquartile range (IQR) exceeding 800. However, the prediction accuracy for lipid and lipid-like molecules, organohalogen compounds, phenylpropanols and polyketides as well as for organic acids and derivatives, is comparatively lower, with all having median scores below 400. The lipid and lipid-like molecules are characterized by a high number of rotatable bonds (on average ≥ 7) and contain additional atoms beyond C, O and H such as P and S. The organic acids superclass shows the lowest median cosine similarity score of 110.5, encompassing most S and P containing molecules in the dataset. Low spectral similarity scores have previously been demonstrated for ODTs . Particularly for those structures containing S and P, the SQM methods show poor accuracy in simulating fragmentation pathways.