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A modified GLM was proposed to explicitly model biological variance and nonbiological noise. Using the expectation and maximization (EM) scheme can distinguish biological variance from noise, termed EMSEV (EM for separating variances). The performance of EMSEV was evaluated by varying noise levels, dimensions of the design matrix, and covariance structures of the target variables. The deviation between EMSEV outputs and the predefined distribution parameters increased with noise level. With a proper initial guess, when the noise magnitude and the variance of the target variables were similar, there were deviations of 3% and 10%\u201316% in the estimated mean and covariance of the target variables, respectively, along with a 1.7% deviation in noise estimation. EMSEV appears promising for distinguishing signal variance from noise in biological systems. 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