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EM algorithms for fitting multistate cure models.

ABSTRACT: Multistate cure models are multistate models in which transitions into one or more of the states cannot occur for a fraction of the population. In the study of cancer, multistate cure models can be used to identify factors related to the rate of cancer recurrence, the rate of death before and after recurrence, and the probability of being cured by initial treatment. However, the previous method for fitting multistate cure models requires substantial custom programming, making these valuable models less accessible to analysts. In this article, we present an Expectation-Maximization (EM) algorithm for fitting the multistate cure model using maximum likelihood. The proposed algorithm makes use of a weighted likelihood representation allowing it to be easily implemented with standard software and can incorporate either parametric or non-parametric baseline hazards for the state transition rates. A common complicating feature in cancer studies is that the follow-up times for recurrence and death may differ. Additionally, we may have missingness in the covariates. We propose a Monte Carlo EM (MCEM) algorithm for fitting the multistate cure model in the presence of covariate missingness and/or unequal follow-up of the two outcomes, we describe a novel approach for obtaining standard errors, and we provide some software. Simulations demonstrate good algorithmic performance as long as the modeling assumptions are sufficiently restrictive. We apply the proposed algorithm to a study of recurrence and death in patients with head and neck cancer.

SUBMITTER: Beesley LJ

PROVIDER: S-EPMC6659172 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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EM algorithms for fitting multistate cure models.

Beesley Lauren J LJ Taylor Jeremy M G JMG

Biostatistics (Oxford, England) 20190701 3

Multistate cure models are multistate models in which transitions into one or more of the states cannot occur for a fraction of the population. In the study of cancer, multistate cure models can be used to identify factors related to the rate of cancer recurrence, the rate of death before and after recurrence, and the probability of being cured by initial treatment. However, the previous method for fitting multistate cure models requires substantial custom programming, making these valuable mode ...[more]

PMID: 29584820

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Project description:Recent advances in instrumentation and software have resulted in cryo-EM rapidly becoming the method of choice for structural biologists, especially for those studying the three-dimensional structures of very large macromolecular complexes. In this contribution, the tools available for macromolecular structure refinement into cryo-EM reconstructions that are available via CCP-EM are reviewed, specifically focusing on REFMAC5 and related tools. Whilst originally designed with a view to refinement against X-ray diffraction data, some of these tools have been able to be repurposed for cryo-EM owing to the same principles being applicable to refinement against cryo-EM maps. Since both techniques are used to elucidate macromolecular structures, tools encapsulating prior knowledge about macromolecules can easily be transferred. However, there are some significant qualitative differences that must be acknowledged and accounted for; relevant differences between these techniques are highlighted. The importance of phases is considered and the potential utility of replacing inaccurate amplitudes with their expectations is justified. More pragmatically, an upper bound on the correlation between observed and calculated Fourier coefficients, expressed in terms of the Fourier shell correlation between half-maps, is demonstrated. The importance of selecting appropriate levels of map blurring/sharpening is emphasized, which may be facilitated by considering the behaviour of the average map amplitude at different resolutions, as well as the utility of simultaneously viewing multiple blurred/sharpened maps. Features that are important for the purposes of computational efficiency are discussed, notably the Divide and Conquer pipeline for the parallel refinement of large macromolecular complexes. Techniques that have recently been developed or improved in Coot to facilitate and expedite the building, fitting and refinement of atomic models into cryo-EM maps are summarized. Finally, a tool for symmetry identification from a given map or coordinate set, ProSHADE, which can identify the point group of a map and thus may be used during deposition as well as during molecular visualization, is introduced.

Dataset Information

EM algorithms for fitting multistate cure models.

Publications

EM algorithms for fitting multistate cure models.

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