Inference in a survival cure model with mismeasured covariates using a simulation-extrapolation approach.
Ontology highlight
ABSTRACT:
SUBMITTER: Bertrand A
PROVIDER: S-EPMC5693403 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDifferent parametric survival models can lead to widely discordant extrapolations and decision uncertainty in cost-effectiveness analyses. The use of excess hazard (EH) methods, which incorporate general population mortality data, has the potential to reduce model uncertainty. This review highlights key practical considerations of EH methods for estimating long-term survival.MethodsDemonstration of methods used a case study of 686 patients from the German Breast Cancer Study Group, followed for a maximum of 7.3 y and divided into low (1/2) and high (3) grade cancers. Seven standard parametric survival models were fit to each group separately. The same 7 distributions were then used in an EH framework, which incorporated general population mortality rates, and fitted both with and without a cure parameter. Survival extrapolations, restricted mean survival time (RMST), and difference in RMST between high and low grades were compared up to 30 years along with Akaike information criterion goodness-of-fit and cure fraction estimates. The sensitivity of the EH models to lifetable misspecification was investigated.ResultsIn our case study, variability in survival extrapolations was extensive across the standard models, with 30-y RMST ranging from 7.5 to 14.3 y. Incorporation of general population mortality rates using EH cure methods substantially reduced model uncertainty, whereas EH models without cure had less of an effect. Long-term treatment effects approached the null for most models but at varying rates. Lifetable misspecification had minimal effect on RMST differences.ConclusionsEH methods may be useful for survival extrapolation, and in cancer, EHs may decrease over time and be easier to extrapolate than all-cause hazards. EH cure models may be helpful when cure is plausible and likely to result in less extrapolation variability.HighlightsIn health economic modeling, to help anchor long-term survival extrapolation, it has been recommended that survival models incorporate background mortality rates using excess hazard (EH) methods.We present a thorough description of EH methods with and without the assumption of cure and demonstrate user-friendly software to aid researchers wishing to use these methods.EH models are applied to a case study, and we demonstrate that EHs are easier to extrapolate and that the use of the EH cure model, when cure is plausible, can reduce extrapolation variability.EH methods are relatively robust to lifetable misspecification.
| S-EPMC10422853 | biostudies-literature
Project description:We explore several approaches for imputing partially observed covariates when the outcome of interest is a censored event time and when there is an underlying subset of the population that will never experience the event of interest. We call these subjects 'cured', and we consider the case where the data are modeled using a Cox proportional hazards (CPH) mixture cure model. We study covariate imputation approaches using fully conditional specification. We derive the exact conditional distribution and suggest a sampling scheme for imputing partially observed covariates in the CPH cure model setting. We also propose several approximations to the exact distribution that are simpler and more convenient to use for imputation. A simulation study demonstrates that the proposed imputation approaches outperform existing imputation approaches for survival data without a cure fraction in terms of bias in estimating CPH cure model parameters. We apply our multiple imputation techniques to a study of patients with head and neck cancer. Copyright © 2016 John Wiley & Sons, Ltd.
| S-EPMC5053880 | biostudies-literature
Project description:To correct for a large number of hypothesis tests, most researchers rely on simple multiple testing corrections. Yet, new methodologies of selective inference could potentially improve power while retaining statistical guarantees, especially those that enable exploration of test statistics using auxiliary information (covariates) to weight hypothesis tests for association. We explore one such method, adaptive P-value thresholding (AdaPT), in the framework of genome-wide association studies (GWAS) and gene expression/coexpression studies, with particular emphasis on schizophrenia (SCZ). Selected SCZ GWAS association P values play the role of the primary data for AdaPT; single-nucleotide polymorphisms (SNPs) are selected because they are gene expression quantitative trait loci (eQTLs). This natural pairing of SNPs and genes allow us to map the following covariate values to these pairs: GWAS statistics from genetically correlated bipolar disorder, the effect size of SNP genotypes on gene expression, and gene-gene coexpression, captured by subnetwork (module) membership. In all, 24 covariates per SNP/gene pair were included in the AdaPT analysis using flexible gradient boosted trees. We demonstrate a substantial increase in power to detect SCZ associations using gene expression information from the developing human prefrontal cortex. We interpret these results in light of recent theories about the polygenic nature of SCZ. Importantly, our entire process for identifying enrichment and creating features with independent complementary data sources can be implemented in many different high-throughput settings to ultimately improve power.
| S-EPMC7334489 | biostudies-literature
Project description:BackgroundExtrapolation of survival data is a key task in health technology assessments (HTAs), which may be improved by incorporating general population mortality data via relative survival models. Dynamic survival models are a promising method for extrapolation that may be expanded to dynamic relative survival models (DRSMs), a novel development presented here. There are currently neither examples of dynamic models in HTA nor comparisons of DRSMs with other relative survival models when used for survival extrapolation.MethodsAn existing appraisal, for which there had been disagreement over the approach to survival extrapolation, was chosen and the health economic model recreated. The sensitivity of estimates of cost-effectiveness to different model choices (standard survival models, DSMs, and DRSMs) and specifications was examined. The appraisal informed a simulation study to evaluate DRSMs with relative survival models based on both standard and spline-based (flexible) models.ResultsDynamic models provided insight into the behavior of the trend in the hazard function and how it may vary during the extrapolated phase. DRSMs led to extrapolations with improved plausibility for which model choice may be based on clinical input. In the simulation study, the flexible and dynamic relative survival models performed similarly and provided highly variable extrapolations.LimitationsFurther experience with these models is required to identify settings when they are most useful, and they provide sufficiently accurate extrapolations.ConclusionsDynamic models provide a flexible and attractive method for extrapolating survival data and facilitate the use of clinical input for model choice. Flexible and dynamic relative survival models make few structural assumptions and can improve extrapolation plausibility, but further research is required into methods for reducing the variability in extrapolations.
| S-EPMC9459356 | biostudies-literature
Project description:Data with high-dimensional covariates are now commonly encountered. Compared to other types of responses, research on high-dimensional data with censored survival responses is still relatively limited, and most of the existing studies have been focused on estimation and variable selection. In this study, we consider data with a censored survival response, a set of low-dimensional covariates of main interest, and a set of high-dimensional covariates that may also affect survival. The accelerated failure time model is adopted to describe survival. The goal is to conduct inference for the effects of low-dimensional covariates, while properly accounting for the high-dimensional covariates. A penalization-based procedure is developed, and its validity is established under mild and widely adopted conditions. Simulation suggests satisfactory performance of the proposed procedure, and the analysis of two cancer genetic datasets demonstrates its practical applicability.
| S-EPMC6502249 | biostudies-literature
Project description:BackgroundThe development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human.MethodThe Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build PBPK models for levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (Gat) ophthalmic solutions. in the rabbit eye. The models were subsequently used to predict Lev, Mox, and Gat exposure after ocular solution administrations in humans. Drug-specific parameters were used as fitted and validated in the rabbit OCAT model. The physiological parameters were scaled to match human ocular physiology.ResultsOCAT model simulations for rabbit well described the observed concentrations in the eye compartments following Lev, Mox, and Gat solution administrations of different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted.ConclusionEven though additional case studies for different types of active pharmaceutical ingredients (APIs) and formulations will be needed, the current study represents an important step in the validation of the extrapolation method to predict human ocular exposure for ophthalmic drug products using PBPK models.
| S-EPMC9944674 | biostudies-literature
Project description:ObjectiveSensitivity analysis for random measurement error can be applied in the absence of validation data by means of regression calibration and simulation-extrapolation. These have not been compared for this purpose.Study design and settingA simulation study was conducted comparing the performance of regression calibration and simulation-extrapolation for linear and logistic regression. The performance of the two methods was evaluated in terms of bias, mean squared error (MSE) and confidence interval coverage, for various values of reliability of the error-prone measurement (0.05-0.91), sample size (125-4000), number of replicates (2-10), and R-squared (0.03-0.75). It was assumed that no validation data were available about the error-free measures, while correct information about the measurement error variance was available.ResultsRegression calibration was unbiased while simulation-extrapolation was biased: median bias was 0.8% (interquartile range (IQR): -0.6;1.7%), and -19.0% (IQR: -46.4;-12.4%), respectively. A small gain in efficiency was observed for simulation-extrapolation (median MSE: 0.005, IQR: 0.004;0.006) versus regression calibration (median MSE: 0.006, IQR: 0.005;0.009). Confidence interval coverage was at the nominal level of 95% for regression calibration, and smaller than 95% for simulation-extrapolation (median coverage: 85%, IQR: 73;93%). The application of regression calibration and simulation-extrapolation for a sensitivity analysis was illustrated using an example of blood pressure and kidney function.ConclusionOur results support the use of regression calibration over simulation-extrapolation for sensitivity analysis for random measurement error.
| S-EPMC10446124 | biostudies-literature
Project description:BackgroundEstimates of life expectancy are a key input to cost-effectiveness analysis (CEA) models for cancer treatments. Due to the limited follow-up in Randomized Controlled Trials (RCTs), parametric models are frequently used to extrapolate survival outcomes beyond the RCT period. However, different parametric models that fit the RCT data equally well may generate highly divergent predictions of treatment-related gain in life expectancy. Here, we investigate the use of information external to the RCT data to inform model choice and estimation of life expectancy.MethodsWe used Bayesian multi-parameter evidence synthesis to combine the RCT data with external information on general population survival, conditional survival from cancer registry databases, and expert opinion. We illustrate with a 5-year follow-up RCT of cetuximab plus radiotherapy v. radiotherapy alone for head and neck cancer.ResultsStandard survival time distributions were insufficiently flexible to simultaneously fit both the RCT data and external data on general population survival. Using spline models, we were able to estimate a model that was consistent with the trial data and all external data. A model integrating all sources achieved an adequate fit and predicted a 4.7-month (95% CrL: 0.4; 9.1) gain in life expectancy due to cetuximab.ConclusionsLong-term extrapolation using parametric models based on RCT data alone is highly unreliable and these models are unlikely to be consistent with external data. External data can be integrated with RCT data using spline models to enable long-term extrapolation. Conditional survival data could be used for many cancers and general population survival may have a role in other conditions. The use of external data should be guided by knowledge of natural history and treatment mechanisms.
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Project description:In clinical or epidemiological follow-up studies, methods based on time scale indicators such as the restricted mean survival time (RMST) have been developed to some extent. Compared with traditional hazard rate indicator system methods, the RMST is easier to interpret and does not require the proportional hazard assumption. To date, regression models based on the RMST are indirect or direct models of the RMST and baseline covariates. However, time-dependent covariates are becoming increasingly common in follow-up studies. Based on the inverse probability of censoring weighting (IPCW) method, we developed a regression model of the RMST and time-dependent covariates. Through Monte Carlo simulation, we verified the estimation performance of the regression parameters of the proposed model. Compared with the time-dependent Cox model and the fixed (baseline) covariate RMST model, the time-dependent RMST model has a better prediction ability. Finally, an example of heart transplantation was used to verify the above conclusions.
| S-EPMC9545070 | biostudies-literature
Project description:Resistive Random Access Memory (RRAM) is a promising technology for power efficient hardware in applications of artificial intelligence (AI) and machine learning (ML) implemented in non-von Neumann architectures. However, there is an unanswered question if the device non-idealities preclude the use of RRAM devices in this potentially disruptive technology. Here we investigate the question for the case of inference. Using experimental results from silicon oxide (SiO x ) RRAM devices, that we use as proxies for physical weights, we demonstrate that acceptable accuracies in classification of handwritten digits (MNIST data set) can be achieved using non-ideal devices. We find that, for this test, the ratio of the high- and low-resistance device states is a crucial determinant of classification accuracy, with ~96.8% accuracy achievable for ratios >3, compared to ~97.3% accuracy achieved with ideal weights. Further, we investigate the effects of a finite number of discrete resistance states, sub-100% device yield, devices stuck at one of the resistance states, current/voltage non-linearities, programming non-linearities and device-to-device variability. Detailed analysis of the effects of the non-idealities will better inform the need for the optimization of particular device properties.
| S-EPMC6582938 | biostudies-literature