Stochastic compartmental models are prevalent tools for describing disease spread, but inference under these models is challenging for many types of surveillance data when the marginal likelihood function becomes intractable due to missing information. To address this, we develop a closed-form likelihood for discretely observed incidence count data under the dynamical survival analysis (DSA) paradigm. The method approximates the stochastic population-level hazard by a large population limit while retaining a count-valued stochastic model, and leads to survival analytic inferential strategies that are both computationally efficient and flexible to model generalizations. Through simulation, we show that parameter estimation is competitive with recent exact but computationally expensive likelihood-based methods in partially observed settings. Previous work has shown that the DSA approximation is generalizable, and we show that the inferential developments here also carry over to models featuring individual heterogeneity, such as frailty models. We consider case studies of both Ebola and COVID-19 data on variants of the model, including a network-based epidemic model and a model with distributions over susceptibility, demonstrating its flexibility and practical utility on real, partially observed datasets.
We present a new method for analyzing stochastic epidemic models under minimal assumptions. The method, dubbed DSA, is based on a simple yet powerful observation, namely that population-level mean-field trajectories described by a system of PDE may also approximate individual-level times of infection and recovery. This idea gives rise to a certain non-Markovian agent-based model and provides an agent-level likelihood function for a random sample of infection and/or recovery times. Extensive numerical analyses on both synthetic and real epidemic data from the FMD in the United Kingdom and the C…
We are concerned with the flexible parametric analysis of bivariate survival data. Elsewhere, we have extolled the virtues of the "power generalized Weibull" (PGW) distribution as an attractive vehicle for univariate parametric survival analysis: it is a tractable, parsimonious, model which interpretably allows for a wide variety of hazard shapes and, when adapted (to give an adapted PGW, or APGW, distribution), covers a wide variety of important special/limiting cases. Here, we additionally observe a frailty relationship between a PGW distribution with one value of the parameter which control…
One goal in survival analysis of right-censored data is to estimate the marginal survival function in the presence of dependent censoring. When many auxiliary covariates are sufficient to explain the dependent censoring, estimation based on either a semiparametric model or a nonparametric model of the conditional survival function can be problematic due to the high dimensionality of the auxiliary information. In this paper, we use two working models to condense these high-dimensional covariates in dimension reduction; then an estimate of the marginal survival function can be derived nonparamet…
Marginal structural models (MSMs) allow for causal analysis of longitudinal data. The MSMs were originally developed as discrete time models. Recently, continuous-time MSMs were presented as a conceptually appealing alternative for survival analysis. In applied analyses, it is often assumed that the theoretical treatment weights are known, but these weights are usually unknown and must be estimated from the data. Here we provide a sufficient condition for a class of continuous-time MSMs to be consistent even when the weights are estimated, and we show how additive hazard models can be used to …
Multilevel network meta-regression for multistate models: Population-adjusted joint synthesis of progression and survival data from individual and aggregate evidence
University of California, San Francisco（旧金山加利福尼亚大学）；UCSF Helen Diller Family Comprehensive Cancer Center（UCSF海伦·迪勒家族综合癌症中心）；The Philip R. Lee Institute for Health Policy Studies（菲利普·李健康政策研究所）；Precision AQ
Joint modelling of longitudinal and time-to-event data is usually described by a joint model which uses shared or correlated latent effects to capture associations between the two processes. Under this framework, the joint distribution of the two processes can be derived straightforwardly by assuming conditional independence given the random effects. Alternative approaches to induce interdependency into sub-models have also been considered in the literature and one such approach is using copulas to introduce non-linear correlation between the marginal distributions of the longitudinal and time…
The Cox regression, a semi-parametric method of survival analysis, is extremely popular in biomedical applications. The proportional hazards assumption is a key requirement in the Cox model. To accommodate non-proportional hazards, we propose to parameterise the shape parameter of the baseline hazard function using the additional, separate Cox-regression term which depends on the vector of the covariates. We call this model the double-Cox model. The R programs for fitting the double-Cox model are available on Github. We formally introduce the double-Cox model with shared frailty and investigat…
This paper studies Cox's regression hazard model with an unobservable random frailty where no specific distribution is postulated for the frailty variable, and the marginal lifetime distribution allows both parametric and non-parametric models. Laplace's approximation method and gradient search on smooth manifolds embedded in Euclidean space are applied, and a non-iterative profile likelihood optimization method is proposed for estimating the regression coefficients. The proposed method is compared with the Expected-Maximization method developed based on a gamma frailty assumption, and also in…
Cluster randomized trials (CRTs) frequently recruit a small number of clusters, therefore necessitating the application of small-sample corrections for valid inference. A recent systematic review indicated that CRTs reporting right-censored, time-to-event outcomes are not uncommon, and that the marginal Cox proportional hazards model is one of the common approaches used for primary analysis. While small-sample corrections have been studied under marginal models with continuous, binary and count outcomes, no prior research has been devoted to the development and evaluation of bias-corrected san…
Spatial survival analysis has received a great deal of attention over the last 20 years due to the important role that geographical information can play in predicting survival. This paper provides an introduction to a set of programs for implementing some Bayesian spatial survival models in R using the package spBayesSurv. The function survregbayes includes the three most commonly-used semiparametric models: proportional hazards, proportional odds, and accelerated failure time. All manner of censored survival times are simultaneously accommodated including uncensored, interval censored, curren…
Motivated by the classical Susceptible-Infected-Recovered (SIR) epidemic models proposed by Kermack and Mckendrick, we consider a class of stochastic compartmental dynamical systems with a notion of partial ordering among the compartments. We call such systems unidirectional Mass Transfer Models (MTMs). We show that there is a natural way of interpreting a uni-directional MTM as a Survival Dynamical System (SDS) that is described in terms of survival functions instead of population counts. This SDS interpretation allows us to employ tools from survival analysis to address various issues with d…
The present article studies survival analytic aspects of semiparametric copula dependence models with arbitrary univariate marginals. The underlying survival functions admit a representation via exponent measures which have an interpretation within the context of hazard functions. In particular, correlated frailty survival models are linked to copulas. Additionally, the relation to exponent measures of minumum-infinitely divisible distributions as well as to the Lévy measure of the Lévy-Khintchine formula is pointed out. The semiparametric character of the current analyses and the construction…
Count data are often subject to underreporting, especially in infectious disease surveillance. We propose an approximate maximum likelihood method to fit count time series models from the endemic-epidemic class to underreported data. The approach is based on marginal moment matching where underreported processes are approximated through completely observed processes from the same class. Moreover, the form of the bias when underreporting is ignored or taken into account via multiplication factors is analysed. Notably, we show that this leads to a downward bias in model-based estimates of the ef…
This article considers ultrahigh-dimensional forecasting problems with survival response variables. We propose a two-step model averaging procedure for improving the forecasting accuracy of the true conditional mean of a survival response variable. The first step is to construct a class of candidate models, each with low-dimensional covariates. For this, a feature screening procedure is developed to separate the active and inactive predictors through a marginal BuckleyCJames index, and to group covariates with a similar index size together to form regression models with survival response varia…
A case-control family study is a study where individuals with a disease of interest (case probands) and individuals without the disease (control probands) are randomly sampled from a well-defined population. Possibly right-censored age at onset and disease status are observed for both probands and their relatives. Correlation among the outcomes within a family is induced by factors such as inherited genetic susceptibility, shared environment, and common behavior patterns. For this setting, we present a nonparametric estimator of the marginal survival function, based on local linear estimation …
Several gene-based association tests for time-to-event traits have been proposed recently, to detect whether a gene region (containing multiple variants), as a set, is associated with the survival outcome. However, for bivariate survival outcomes, to the best of our knowledge, there is no statistical method that can be directly applied for gene-based association analysis. Motivated by a genetic study to discover gene regions associated with the progression of a bilateral eye disease, Age-related Macular Degeneration (AMD), we implement a novel functional regression method under the copula fram…
Investigating the causal relationship between exposure and the time-to-event outcome is an important topic in biomedical research. Previous literature has discussed the potential issues of using the hazard ratio as a marginal causal effect measure due to its noncollapsibility property. In this paper, we advocate using the restricted mean survival time (RMST) difference as the marginal causal effect measure, which is collapsible and has a simple interpretation as the difference of area under survival curves over a certain time horizon. To address both measured and unmeasured confounding, a matc…
Unobserved individual heterogeneity is a common challenge in population cancer survival studies. This heterogeneity is usually associated with the combination of model misspecification and the failure to record truly relevant variables. We investigate the effects of unobserved individual heterogeneity in the context of excess hazard models, one of the main tools in cancer epidemiology. We propose an individual excess hazard frailty model to account for individual heterogeneity. This represents an extension of frailty modelling to the relative survival framework. In order to facilitate the infe…
Longitudinal observational patient data can be used to investigate the causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for controlling for the time-dependent confounding that typically occurs. The most commonly used is inverse probability weighted estimation of marginal structural models (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, in particular in combination with the target trial emulation framework. This approach involves creating a sequence of `trials' from new time origins, restricting to indi…
Bayesian nonparametric marginal methods are very popular since they lead to fairly easy implementation due to the formal marginalization of the infinite-dimensional parameter of the model. However, the straightforwardness of these methods also entails some limitations: they typically yield point estimates in the form of posterior expectations, but cannot be used to estimate non-linear functionals of the posterior distribution, such as median, mode or credible intervals. This is particularly relevant in survival analysis where non-linear functionals such as e.g. the median survival time, play a…
Antibodies, an essential part of our immune system, develop through an intricate process to bind a wide array of pathogens. This process involves randomly mutating DNA sequences encoding these antibodies to find variants with improved binding, though mutations are not distributed uniformly across sequence sites. Immunologists observe this nonuniformity to be consistent with "mutation motifs", which are short DNA subsequences that affect how likely a given site is to experience a mutation. Quantifying the effect of motifs on mutation rates is challenging: a large number of possible motifs makes…
Motivation: The discovery of relationships between gene expression measurements and phenotypic responses is hampered by both computational and statistical impediments. Conventional statistical methods are less than ideal because they either fail to select relevant genes, predict poorly, ignore the unknown interaction structure between genes, or are computationally intractable. Thus, the creation of new methods which can handle many expression measurements on relatively small numbers of patients while also uncovering gene-gene relationships and predicting well is desirable. Results: We develop …
Contrasting marginal counterfactual survival curves across treatment arms is an effective and popular approach for inferring the causal effect of an intervention on a right-censored time-to-event outcome. A key challenge to drawing such inferences in observational settings is the possible existence of unmeasured confounding, which may invalidate most commonly used methods that assume no hidden confounding bias. In this paper, rather than making the standard no unmeasured confounding assumption, we extend the recently proposed proximal causal inference framework of Miao et al. (2018), Tchetgen …
The UK Biobank is a large-scale health resource comprising genetic, environmental and medical information on approximately 500,000 volunteer participants in the UK, recruited at ages 40--69 during the years 2006--2010. The project monitors the health and well-being of its participants. This work demonstrates how these data can be used to estimate in a semi-parametric fashion the effects of genetic and environmental risk factors on the hazard functions of various diseases, such as colorectal cancer. An illness-death model is adopted, which inherently is a semi-competing risks model, since death…
We propose a new class of multivariate survival models based on archimedean copulas with margins modeled by the Yang and Prentice (YP) model. The Ali-Mikhail-Haq (AMH), Clayton, Frank, Gumbel-Hougaard (GH), and Joe copulas are employed to accommodate the dependency among marginal distributions. Baseline distributions are modeled semiparametrically by the piecewise exponential (PE) distribution and the Bernstein polynomials. The new class of models possesses some attractive features: i) the ability to take into account survival data with crossing survival curves; ii) the inclusion of the well-k…
Survival models are used to analyze time-to-event data in a variety of disciplines. Proportional hazard models provide interpretable parameter estimates, but proportional hazards assumptions are not always appropriate. Non-parametric models are more flexible but often lack a clear inferential framework. We propose a Bayesian tree partition model which is both flexible and inferential. Inference is obtained through the posterior tree structure and flexibility is preserved by modeling the the hazard function in each partition using a latent exponentiated Gaussian process. An efficient reversible…
Databases derived from electronic health records (EHRs) are commonly subject to left truncation, a type of selection bias induced due to patients needing to survive long enough to satisfy certain entry criteria. Standard methods to adjust for left truncation bias rely on an assumption of marginal independence between entry and survival times, which may not always be satisfied in practice. In this work, we examine how a weaker assumption of conditional independence can result in unbiased estimation of common statistical parameters. In particular, we show the estimability of conditional paramete…
Recent advances in causal mediation analysis have formalized conditions for estimating direct and indirect effects in various contexts. These approaches have been extended to a number of models for survival outcomes including accelerated failure time (AFT) models which are widely used in a broad range of health applications given their intuitive interpretation. In this setting, it has been suggested that under standard assumptions, the "difference" and "product" methods produce equivalent estimates of the indirect effect of exposure on the survival outcome. We formally show that these two meth…
For the analysis of clustered survival data, two different types of models that take the association into account, are commonly used: frailty models and copula models. Frailty models assume that conditional on a frailty term for each cluster, the hazard functions of individuals within that cluster are independent. These unknown frailty terms with their imposed distribution are used to express the association between the different individuals in a cluster. Copula models on the other hand assume that the joint survival function of the individuals within a cluster is given by a copula function, e…
