## parallelizable sampling method for parameter inference of large biochemical reaction models

**I** came across this older (2016) arXiv paper by Jan Mikelson and Mustafa Khammash [antidated as of April 25, 2018] as another version of nested sampling. The novelty of the approach is in applying nested sampling for approximating the likelihood function in the case of involved hidden Markov models (although the name itself does not appear in the paper). This is an interesting proposal, even though there is a fairly large and very active literature on computational approaches to such objects, from sequential Monte Carlo (SMC) to particle MCMC (pMCMC), to SMC².

“We found a way to efficiently sample parameter vectors (particles) from the super level set of the likelihood (sets of particles with a likelihood equal to or higher than some threshold) corresponding to an increasing sequence of thresholds” (p.2)

The approach here is an aggregate of nested sampling and particle filters (SMC), filters that are paradoxically employed in approximating the likelihood function itself, thus called repeatedly as the value of the parameter θ changes, unless I am confused, when it seems to me that, once started with particle filters, the authors could have used them all the way to the upper level (through, again, SMC²). Instead, and that brings a further degree of (uncorrected) approximation to the procedure, a Dirichlet process prior is used to estimate Gaussian mixture approximations to the true posterior distribution(s) on the (super) level sets. Now, approximating a distribution that is zero outside a compact set [the prior restricted to the likelihood being larger than by a distribution with an infinite support does not a priori sound like a particularly enticing idea. Note also that there is no later correction for using the mixture approximation to the restricted prior. (The method also involves an approximation of the (Lebesgue) volume of the level sets that may be poor in higher dimensions.)

“DP-GMM estimations work very well in high dimensional spaces and since we use rejection sampling to obtain samples from the level set by sampling from the DP-GMM estimation, the estimation error does not get propagated through iterations.” (p.13)

One aspect of the paper that puzzles me is the use of a rejection sampler to produce new parameters simulations from a given (super) level set, as this involves a lower bound M on the Gaussian mixture approximation over this level set. If a Gaussian mixture approximation is available, there is apparently no need for this as it can be sampled directly and values below the threshold can be disposed of. It is also unclear why the error does not propagate from one level to the next, if only because of the connection between the successive particle approximations.

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