An improved fully connected hidden Markov model for rational vaccine design
Large-scale, in vitro vaccine screening is an expensive and slow process, while rational vaccine design is faster and cheaper. As opposed to the emperical ways to design vaccines in biology laboratories, rational vaccine design models the structure of vaccines with computational approaches. Building an effective predictive computer model requires extensive knowledge of the process or phenomenon being modelled. Given current knowledge about the steps involved in immune system responses, computer models are currently focused on one or two of the most important and best known steps; for example: presentation of antigens by major histo-compatibility complex (MHC) molecules. In this step, the MHC molecule selectively binds to some peptides derived from antigens and then presents them to the T-cell. One current focus in rational vaccine design is prediction of peptides that can be bound by MHC. Theoretically, predicting which peptides bind to a particular MHC molecule involves discovering patterns in known MHC-binding peptides and then searching for peptides which conform to these patterns in some new antigenic protein sequences. According to some previous work, Hidden Markov models (HMMs), a machine learning technique, is one of the most effective approaches for this task. Unfortunately, for computer models like HMMs, the number of the parameters to be determined is larger than the number which can be estimated from available training data. Thus, heuristic approaches have to be developed to determine the parameters. In this research, two heuristic approaches are proposed. The first initializes the HMM transition and emission probability matrices by assigning biological meanings to the states. The second approach tailors the structure of a fully connected HMM (fcHMM) to increase specificity. The effectiveness of these two approaches is tested on two human leukocyte antigens(HLA) alleles, HLA-A*0201 and HLAB* 3501. The results indicate that these approaches can improve predictive accuracy. Further, the HMM implementation incorporating the above heuristics can outperform a popular profile HMM (pHMM) program, HMMER, in terms of predictive accuracy.
DegreeMaster of Science (M.Sc.)
SupervisorKusalik, Anthony J. (Tony)
CommitteeZhang, W. J. (Chris); Daley, Mark; Bickis, Mikelis G.; Babiuk, Lorne A.
Copyright DateFebruary 2005
heuristic matrix initialization
fully connected hidden markov model
rational vaccine design