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CPS2233 Sharon Lee
            Where   and   are independent random effects (RE) terms that govern
                     
                             
            the scaling and translation of µ   from µ , respectively. These RE terms are
                                                     
            independently distributed as
                                           ~ (1 ,  )
                                            
                                                 
                                                       
                                                    
            and
                                             ~(0,  )
                                             
                                                      
            Where    =  1  and 1 , is a -dimensional vector with all elements being
                                     
                            
            one. It follows that the batch template has a mixture of MST distributions with
            component distributions given by

             (µ ,  ,  ,  )  for   = 1, … ,  .  This  template  is  useful  not  only  as  a
                
                    
                      
                            
                         
            representative summary of the batch that facilitates visualization, but can be a
            powerful tool in downstream analyses such as across-batch comparisons and
            new sample classification. The latter can assist in clinical diagnosis of diseases.

            Fitting the Hcyto model
            The  expectation-maximization  (EM)  algorithm  (Dempster  et  al.,  1977)  has
            become a standard tool for carrying out maximum likelihood estimation of the
            parameters of finite mixture models. As both the lower- and upper- levels of
            Hcyto can be written as a mixture model, these models can be fitted via the
            EM algorithm. The technical details are omitted due to length restrictions, but
            the  procedure  for  the  lower-level  models  are  similar  to  that  for  the  MST
            mixture model by Pyne et al. (2009). They can be expressed in a hierarchical
            form involving a normal, a gamma, and a half normal random variable. With
            the upper-level, a further layer is added to this hierarchical form, leading to
                            |µ ,   ,   ,   ~ (µ +  |  |,  )
                                                       
                                                    
                                                                      
                                                            
                                
                            
                                                          
                                   µ |  ~ (µ ,    +  )
                                                  
                                              
                                                         
                                                               
                                                      
                                    
                                        |  ,   ~(0,1)
                                                          
                                        |  ~( , )
                                                         2 2
                                           ~ ( )
                                                        
                                                    
            where  is the diagonal matrix with diagonal elements given by µ ,   is the
                                                                             
                                                                                 
            diagonal  matrix  given  by    ,    denotes  the  (univariate)  half-normal
                                          
            distribution,  Gamma(·)  denotes  the  gamma  distribution,  and   ( )
                                                                                 
                                                                                     
            denotes  the  multinomial  distribution  with    categories  and  probabilities
                                    
               = ( 1 ,  2 , … ,   )  . Note that although the Hcyto model consists of
            two levels, the model fitting procedure simultaneously estimate all parameters
            of the model (that is, including both the lower and upper levels) in a single
            step. No pre-processing or post-hoc steps are required.



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