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Register a new userEstimation of cell lineage trees by maximum-likelihood phylogenetics
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CRISPR technology has enabled large-scale cell lineage tracing for complex multicellular organisms by mutating synthetic genomic barcodes during organismal development. However, these sophisticated biological tools currently use ad-hoc and outmoded computational methods to reconstruct the cell lineage tree from the mutated barcodes. Because these methods are agnostic to the biological mechanism, they are unable to take full advantage of the datas structure. We propose a statistical model for the mutation process and develop a procedure to estimate the tree topology, branch lengths, and mutation parameters by iteratively applying penalized maximum likelihood estimation. In contrast to existing techniques, our method estimates time along each branch, rather than number of mutation events, thus providing a detailed account of tissue-type differentiation. Via simulations, we demonstrate that our method is substantially more accurate than existing approaches. Our reconstructed trees also better recapitulate known aspects of zebrafish development and reproduce similar results across fish replicates.
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Tuffley and Steel (1997) proved that Maximum Likelihood and Maximum Parsimony methods in phylogenetics are equivalent for sequences of characters under a simple symmetric model of substitution with no common mechanism. This result has been widely cited ever since. We show that small changes to the model assumptions suffice to make the two methods inequivalent. In particular, we analyze the case of bounded substitution probabilities as well as the molecular clock assumption. We show that in these cases, even under no common mechanism, Maximum Parsimony and Maximum Likelihood might make conflicting choices. We also show that if there is an upper bound on the substitution probabilities which is `sufficiently small, every Maximum Likelihood tree is also a Maximum Parsimony tree (but not vice versa).
The random coefficients model $Y_i={beta_0}_i+{beta_1}_i {X_1}_i+{beta_2}_i {X_2}_i+ldots+{beta_d}_i {X_d}_i$, with $mathbf{X}_i$, $Y_i$, $mathbf{beta}_i$ i.i.d, and $mathbf{beta}_i$ independent of $X_i$ is often used to capture unobserved heterogeneity in a population. We propose a quasi-maximum likelihood method to estimate the joint density distribution of the random coefficient model. This method implicitly involves the inversion of the Radon transformation in order to reconstruct the joint distribution, and hence is an inverse problem. Nonparametric estimation for the joint density of $mathbf{beta}_i=({beta_0}_i,ldots, {beta_d}_i)$ based on kernel methods or Fourier inversion have been proposed in recent years. Most of these methods assume a heavy tailed design density $f_mathbf{X}$. To add stability to the solution, we apply regularization methods. We analyze the convergence of the method without assuming heavy tails for $f_mathbf{X}$ and illustrate performance by applying the method on simulated and real data. To add stability to the solution, we apply a Tikhonov-type regularization method.
We consider the problem of estimating parameters of stochastic differential equations (SDEs) with discrete-time observations that are either completely or partially observed. The transition density between two observations is generally unknown. We propose an importance sampling approach with an auxiliary parameter when the transition density is unknown. We embed the auxiliary importance sampler in a penalized maximum likelihood framework which produces more accurate and computationally efficient parameter estimates. Simulation studies in three different models illustrate promising improvements of the new penalized simulated maximum likelihood method. The new procedure is designed for the challenging case when some state variables are unobserved and moreover, observed states are sparse over time, which commonly arises in ecological studies. We apply this new approach to two epidemics of chronic wasting disease in mule deer.
In this paper we present a novel method for estimating the parameters of a parametric diffusion processes. Our approach is based on a closed-form Maximum Likelihood estimator for an approximating Continuous Time Markov Chain (CTMC) of the diffusion process. Unlike typical time discretization approaches, such as psuedo-likelihood approximations with Shoji-Ozaki or Kesslers method, the CTMC approximation introduces no time-discretization error during parameter estimation, and is thus well-suited for typical econometric situations with infrequently sampled data. Due to the structure of the CTMC, we are able to obtain closed-form approximations for the sample likelihood which hold for general univariate diffusions. Comparisons of the state-discretization approach with approximate MLE (time-discretization) and Exact MLE (when applicable) demonstrate favorable performance of the CMTC estimator. Simulated examples are provided in addition to real data experiments with FX rates and constant maturity interest rates.
We are frequently faced with a large collection of antibodies, and want to select those with highest affinity for their cognate antigen. When developing a first-line therapeutic for a novel pathogen, for instance, we might look for such antibodies in patients that have recovered. There exist effective experimental methods of accomplishing this, such as cell sorting and baiting; however they are time consuming and expensive. Next generation sequencing of B cell receptor (BCR) repertoires offers an additional source of sequences that could be tapped if we had a reliable method of selecting those coding for the best antibodies. In this paper we introduce a method that uses evolutionary information from the family of related sequences that share a naive ancestor to predict the affinity of each resulting antibody for its antigen. When combined with information on the identity of the antigen, this method should provide a source of effective new antibodies. We also introduce a method for a related task: given an antibody of interest and its inferred ancestral lineage, which branches in the tree are likely to harbor key affinity-increasing mutations? These methods are implemented as part of continuing development of the partis BCR inference package, available at https://github.com/psathyrella/partis.
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