Ramola, R.; De Paolis Klauza, M. C.; Piovesan, D.; Peng, Y.; Joshi, P.; Mehdiabadi, M.; Quaglia, F.; Pancsa, R.; Chemes, L. B.; Ahmadi, M.; Ahn, H.; Altenhoff, A. M.; Asgari, E.; Aspromonte, M. C.; Atalay, V.; Babbi, G.; Baldazzi, D.; Barot, M. M.; Ben-Hur, A.; Benso, A.; Berenberg, D.; Bjorne, J.; Boecker, F.; Boldi, P.; Bonello, J.; Bordin, N.; Borole, P.; Ebrahimpour Boroojeny, A.; Cao, R.; Di Carlo, S.; Casadio, R.; Casiraghi, E.; Chang, J.-M.; Chen, C.; Chen, T.-M.; Cheng, J.; Chiu, S.; Dalkiran, A.; Davidovic, R. S.; Dessimoz, C.; Diao, R.; Djeddi, W. E.; Dogan, T.; Flannery, S. T.; Font

Background: The Critical Assessment of Functional Annotation (CAFA) is a community effort held to understand the field of computational protein function prediction. Every three years, since 2010, the organizers initiate an experiment to collect function predictions on a large set of proteins and then evaluate the performance of predicting methods on a subset of proteins that have accumulated experimental annotations between the submission deadline and the evaluation time. CAFA provides an independent and rigorous assessment of the current state of the art, thus leveling the playing field, highlighting successes, revealing bottlenecks, and offering a forum for the exchange of ideas in protein science. Here, we report the results of the fourth CAFA experiment (CAFA4). Results: CAFA4 featured the participation of 148 methods from 70 research groups on a total of 46,205 unique proteins over a 5-year annotation accumulation phase, the longest in any CAFA. In a comparison across CAFA2-CAFA4 methods, the prediction of Gene Ontology (GO) terms has clearly improved across all three GO aspects and traditional evaluation settings. While not achieving the first rank, several CAFA2 and CAFA3 methods featured in the top ten methods in many evaluations, suggesting that earlier methods still hold relevance. The performance is weaker in the newly introduced "partial knowledge" evaluation category (proteins with experimental annotations before submission deadline that gained additional annotations in the same GO aspect during the annotation accumulation phase), highlighting the need for a new class of methods. The rankings of the methods were stable over the years in traditional evaluation settings, but less so in the new partial knowledge evaluation. Overall, the field continues to progress with some influx of new participants. Sustained efforts will be necessary to substantially advance it.