Building Cox-Type Structured Hazard Regression Models with Time-Varying Effects

In recent years, flexible hazard regression models based on penalised splines have been developed that allow us to extend the classical Cox-model via the inclusion of time-varying and nonparametric effects. Despite their immediate appeal in terms of flexibility, these models introduce additional difficulties when a subset of covariates and the corresponding modelling alternatives have to be chosen. We present an analysis of data from a specific patient population with 90-day survival as the response variable. The aim is to determine a sensible prognostic model where some variables have to be included due to subject-matter knowledge while other variables are subject to model selection. Motivated by this application, we propose a twostage stepwise model building strategy to choose both the relevant covariates and the corresponding modelling alternatives within the choice set of possible covariates simultaneously. For categorical covariates, competing modelling approaches are linear effects and time-varying effects, whereas nonparametric modelling provides a further alternative in case of continuous covariates. In our data analysis, we identified a prognostic model containing both smooth and time-varying effects

Bayesian Semiparametric Multi-State Models

Multi-state models provide a unified framework for the description of the evolution of discrete phenomena in continuous time. One particular example are Markov processes which can be characterised by a set of time-constant transition intensities between the states. In this paper, we will extend such parametric approaches to semiparametric models with flexible transition intensities based on Bayesian versions of penalised splines. The transition intensities will be modelled as smooth functions of time and can further be related to parametric as well as nonparametric covariate effects. Covariates with time-varying effects and frailty terms can be included in addition. Inference will be conducted either fully Bayesian using Markov chain Monte Carlo simulation techniques or empirically Bayesian based on a mixed model representation. A counting process representation of semiparametric multi-state models provides the likelihood formula and also forms the basis for model validation via martingale residual processes. As an application, we will consider human sleep data with a discrete set of sleep states such as REM and Non-REM phases. In this case, simple parametric approaches are inappropriate since the dynamics underlying human sleep are strongly varying throughout the night and individual-specific variation has to be accounted for using covariate information and frailty terms

Bayesian Semiparametric Multi-State Models

Multi-state models provide a unified framework for the description of the evolution of discrete phenomena in continuous time. One particular example are Markov processes which can be characterised by a set of time-constant transition intensities between the states. In this paper, we will extend such parametric approaches to semiparametric models with flexible transition intensities based on Bayesian versions of penalised splines. The transition intensities will be modelled as smooth functions of time and can further be related to parametric as well as nonparametric covariate effects. Covariates with time-varying effects and frailty terms can be included in addition. Inference will be conducted either fully Bayesian using Markov chain Monte Carlo simulation techniques or empirically Bayesian based on a mixed model representation. A counting process representation of semiparametric multi-state models provides the likelihood formula and also forms the basis for model validation via martingale residual processes. As an application, we will consider human sleep data with a discrete set of sleep states such as REM and Non-REM phases. In this case, simple parametric approaches are inappropriate since the dynamics underlying human sleep are strongly varying throughout the night and individual-specific variation has to be accounted for using covariate information and frailty terms

Bayesian semiparametric multi-state models

Multi-state models provide a unified framework for the description of the evolution of discrete phenomena in continuous time. One particular example is Markov processes which can be characterised by a set of time-constant transition intensities between the states. In this paper, we will extend such parametric approaches to semiparametric models with flexible transition intensities based on Bayesian versions of penalised splines. The transition intensities will be modelled as smooth functions of time and can further be related to parametric as well as nonparametric covariate effects. Covariates with time-varying effects and frailty terms can be included in addition. Inference will be conducted either fully Bayesian (using Markov chain Monte Carlo simulation techniques) or empirically Bayesian (based on a mixed model representation). A counting process representation of semiparametric multi-state models provides the likelihood formula and also forms the basis for model validation via martingale residual processes. As an application, we will consider human sleep data with a discrete set of sleep states such as REM and non-REM phases. In this case, simple parametric approaches are inappropriate since the dynamics underlying human sleep are strongly varying throughout the night and individual specific variation has to be accounted for using covariate information and frailty terms

Childhood mortality in sub-Saharan Africa : cross-sectional insight into small-scale geographical inequalities from Census data

Objectives To estimate and quantify childhood mortality, its spatial correlates and the impact of potential correlates using recent census data from three sub-Saharan African countries (Rwanda, Senegal and Uganda), where evidence is lacking. Design Cross-sectional. Setting Nation-wide census samples from three African countries participating in the 2010 African Census round. All three countries have conducted recent censuses and have information on mortality of children under 5 years. Participants 111 288 children under the age of 5 years in three countries. Primary and secondary outcome measures Under-five mortality was assessed alongside potential correlates including geographical location (where children live), and environmental, bio-demographic and socioeconomic variables. Results Multivariate analysis indicates that in all three countries the overall risk of child death in the first 5 years of life has decreased in recent years (Rwanda: HR=0.04, 95% CI 0.02 to 0.09; Senegal: HR=0.02 (95% CI 0.02 to 0.05); Uganda: HR=0.011 (95% CI 0.006 to 0.018). In Rwanda, lower deaths were associated with living in urban areas (0.79, 0.73, 0.83), children with living mother (HR=0.16, 95% CI 0.15 to 0.17) or living father (HR=0.38, 95% CI 0.36 to 0.39). Higher death was associated with male children (HR=1.06, 95% CI 1.02 to 1.08) and Christian children (HR=1.14, 95% CI 1.05 to 1.27). Children less than 1 year were associated with higher risk of death compared to older children in the three countries. Also, there were significant spatial variations showing inequalities in children mortality by geographic location. In Uganda, for example, areas of high risk are in the south-west and north-west and Kampala district showed a significantly reduced risk. Conclusions We provide clear evidence of considerable geographical variation of under-five mortality which is unexplained by factors considered in the data. The resulting under-five mortality maps can be used as a practical tool for monitoring progress within countries for the Millennium Development Goal 4 to reduce under-five mortality in half by 2015

Weibull regression with Bayesian variable selection to identify prognostic tumour markers of breast cancer survival.

As data-rich medical datasets are becoming routinely collected, there is a growing demand for regression methodology that facilitates variable selection over a large number of predictors. Bayesian variable selection algorithms offer an attractive solution, whereby a sparsity inducing prior allows inclusion of sets of predictors simultaneously, leading to adjusted effect estimates and inference of which covariates are most important. We present a new implementation of Bayesian variable selection, based on a Reversible Jump MCMC algorithm, for survival analysis under the Weibull regression model. A realistic simulation study is presented comparing against an alternative LASSO-based variable selection strategy in datasets of up to 20,000 covariates. Across half the scenarios, our new method achieved identical sensitivity and specificity to the LASSO strategy, and a marginal improvement otherwise. Runtimes were comparable for both approaches, taking approximately a day for 20,000 covariates. Subsequently, we present a real data application in which 119 protein-based markers are explored for association with breast cancer survival in a case cohort of 2287 patients with oestrogen receptor-positive disease. Evidence was found for three independent prognostic tumour markers of survival, one of which is novel. Our new approach demonstrated the best specificity.PJN and SR were funded by the Medical Research Council. PJN also acknowledges partial support from the NIHR Cambridge Biomedical Research Centre.This is the accepted manuscript. The final version is available from SAGE at http://dx.doi.org/10.1177/096228021454874

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer : development of a prognostic model through a crowdsourced challenge with open clinical trial data

Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.Peer reviewe

A Modification Of The EM Algorithm To Estimate An Andersen-Gill Gamma Frailty Model For Multivariate Failure Time Data

A modification of the Andersen-Gill gamma shared frailty model is presented. The variance of the frailty is directly modeled by means of a generalized linear model, the EM algorithm is modified in order to simultaneously estimate a semiparametric model for the failure times and a model for the variance of the frailty. A simulation study is conducted to evaluate the performance of the proposed algorithm (EMB algorithm) and compared with other methods, a marginal model, and a conditional model. Multivariate data from a nosocomial infection study is used to illustrate the methods. The EMB fit turned out to be better than the fit obtained from a marginal model or from a conditional model. The EMB provided the best fit (being the least over-dispersed and having the highest AIC and the highest pseudo-R square) and estimated the parameters most efficiently. The proposed method is able to capture and to take into account unobservable random effects in semiparametric models