Contributions méthodologiques à l’estimation de la survie nette : comparaison des estimateurs et tests des hypothèses du modèle du taux en excès

Net survival is one of the most important indicators in cancer epidemiology. It is defined as the survival that would be observed if cancer were the only cause of death. This is the only one indicator allowing comparisons of cancer impact between countries or time periods because it is not influenced by death because of other causes. The first objective of this work was to compare the performance of several estimators of the net survival in a simulation study and then on real data in order to promote unbiased methods. Those methods are the non-parametric Pohar-Perme method and the parametric multivariable excess rate model. The latest one needs a model building strategy. The use of diagnostic procedures for model checking is an essential part of the modeling process. The second objective was to develop a tool box composed of diagnostic tools allowing to check hypothesis usually considered when constructing an excess mortality rate model, that is, the proportionality or not of the effect of covariates, their functional form and the link function. The third objective deals with the study of the impact of prognostic variables, such as stage at diagnosis, on conditional net survival, that is, on the dynamic of the excess hazard mortality after the diagnosis of colon cancerLa survie nette est un indicateur très utilisé en épidémiologie des cancers. Il s'agit de la survie que l'on observerait si la seule cause de mortalité était le cancer ; il est le seul indicateur épidémiologique utilisable à des fins de comparaisons de survie (entre périodes/pays) car il s'affranchit des éventuelles différences de mortalité dues aux autres causes que le cancer. Le premier objectif de notre travail était d'analyser les performances des différentes méthodes d'estimation de la survie nette sur données simulées ainsi que sur données réelles afin que les méthodes non biaisées soient reconnues scientifiquement et soient les seules à être utilisées par la suite. Nous avons ainsi démontré que deux approches étaient capables d'estimer sans biais la survie nette : l'approche non paramétrique de Pohar-Perme et l'approche reposant sur une modélisation multivariée du taux de mortalité en excès dû au cancer. Cette dernière approche impose une stratégie de construction difficile à mettre en place. Le deuxième objectif était de développer une boîte à outils composée de différents tests permettant de vérifier les différentes hypothèses faites lors de la construction d'un modèle de régression du taux de mortalité en excès. Ces hypothèses concernent habituellement la proportionnalité ou non de l'effet des covariables, leur forme fonctionnelle, ainsi que la fonction de lien utilisée. Le troisième objectif était une application épidémiologique qui visait à étudier l'impact des facteurs pronostiques, tel que le stade au diagnostic, sur la survie nette conditionnelle, en d'autres termes sur la dynamique du taux de mortalité en excès, après la survenue d'un cancer du côlo

Flexible and structured survival model for a simultaneous estimation of non-linear and non-proportional effects and complex interactions between continuous variables: Performance of this multidimensional penalized spline approach in net survival trend analysis.

Cancer survival trend analyses are essential to describe accurately the way medical practices impact patients' survival according to the year of diagnosis. To this end, survival models should be able to account simultaneously for non-linear and non-proportional effects and for complex interactions between continuous variables. However, in the statistical literature, there is no consensus yet on how to build such models that should be flexible but still provide smooth estimates of survival. In this article, we tackle this challenge by smoothing the complex hypersurface (time since diagnosis, age at diagnosis, year of diagnosis, and mortality hazard) using a multidimensional penalized spline built from the tensor product of the marginal bases of time, age, and year. Considering this penalized survival model as a Poisson model, we assess the performance of this approach in estimating the net survival with a comprehensive simulation study that reflects simple and complex realistic survival trends. The bias was generally small and the root mean squared error was good and often similar to that of the true model that generated the data. This parametric approach offers many advantages and interesting prospects (such as forecasting) that make it an attractive and efficient tool for survival trend analyses

High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia

In acute myeloid leukemia (AML), risk stratification based on cytogenetics and mutation profiling is essential but remains insufficient to select the optimal therapy. Accurate biomarkers are needed to improve prognostic assessment. We analyzed RNA sequencing and survival data of 430 AML patients and identified HMGA2 as a novel prognostic marker. We validated a quantitative PCR test to study the association of HMGA2 expression with clinical outcomes in 358 AML samples. In this training cohort, HMGA2 was highly expressed in 22.3% of AML, mostly in patients with intermediate or adverse cytogenetics. High expression levels of HMGA2 (H + ) were associated with a lower frequency of complete remission (58.8% vs 83.4%, P < 0.001), worse 3-year overall survival (OS, 13.2% vs 43.5%, P < 0.001) and relapse-free survival (RFS, 10.8% vs 44.2%, P < 0.001). A positive HMGA2 test also identified a subgroup of patients unresponsive to standard treatments. Multivariable analyses showed that H + was independently associated with significantly worse OS and RFS, including in the intermediate cytogenetic risk category. These associations were confirmed in a validation cohort of 260 patient samples from the UK NCRI AML17 trial. The HMGA2 test could be implemented in clinical trials developing novel therapeutic strategies for high-risk AML

Methodological contribution to net survival estimation : estimator comparison and test of the parametric hazard model assumption

La survie nette est un indicateur très utilisé en épidémiologie des cancers. Il s'agit de la survie que l'on observerait si la seule cause de mortalité était le cancer ; il est le seul indicateur épidémiologique utilisable à des fins de comparaisons de survie (entre périodes/pays) car il s'affranchit des éventuelles différences de mortalité dues aux autres causes que le cancer. Le premier objectif de notre travail était d'analyser les performances des différentes méthodes d'estimation de la survie nette sur données simulées ainsi que sur données réelles afin que les méthodes non biaisées soient reconnues scientifiquement et soient les seules à être utilisées par la suite. Nous avons ainsi démontré que deux approches étaient capables d'estimer sans biais la survie nette : l'approche non paramétrique de Pohar-Perme et l'approche reposant sur une modélisation multivariée du taux de mortalité en excès dû au cancer. Cette dernière approche impose une stratégie de construction difficile à mettre en place. Le deuxième objectif était de développer une boîte à outils composée de différents tests permettant de vérifier les différentes hypothèses faites lors de la construction d'un modèle de régression du taux de mortalité en excès. Ces hypothèses concernent habituellement la proportionnalité ou non de l'effet des covariables, leur forme fonctionnelle, ainsi que la fonction de lien utilisée. Le troisième objectif était une application épidémiologique qui visait à étudier l'impact des facteurs pronostiques, tel que le stade au diagnostic, sur la survie nette conditionnelle, en d'autres termes sur la dynamique du taux de mortalité en excès, après la survenue d'un cancer du côlonNet survival is one of the most important indicators in cancer epidemiology. It is defined as the survival that would be observed if cancer were the only cause of death. This is the only one indicator allowing comparisons of cancer impact between countries or time periods because it is not influenced by death because of other causes. The first objective of this work was to compare the performance of several estimators of the net survival in a simulation study and then on real data in order to promote unbiased methods. Those methods are the non-parametric Pohar-Perme method and the parametric multivariable excess rate model. The latest one needs a model building strategy. The use of diagnostic procedures for model checking is an essential part of the modeling process. The second objective was to develop a tool box composed of diagnostic tools allowing to check hypothesis usually considered when constructing an excess mortality rate model, that is, the proportionality or not of the effect of covariates, their functional form and the link function. The third objective deals with the study of the impact of prognostic variables, such as stage at diagnosis, on conditional net survival, that is, on the dynamic of the excess hazard mortality after the diagnosis of colon cance

Estimating net survival: the importance of allowing for informative censoring.

Net survival, the one that would be observed if cancer were the only cause of death, is the most appropriate indicator to compare cancer mortality between areas or countries. Several parametric and non-parametric methods have been developed to estimate net survival, particularly when the cause of death is unknown. These methods are based either on the relative survival ratio or on the additive excess hazard model, the latter using the general population mortality hazard to estimate the excess mortality hazard (the hazard related to net survival). The present work used simulations to compare estimator abilities to estimate net survival in different settings such as the presence/absence of an age effect on the excess mortality hazard or on the potential time of follow-up, knowing that this covariate has an effect on the general population mortality hazard too. It showed that when age affected the excess mortality hazard, most estimators, including specific survival, were biased. Only two estimators were appropriate to estimate net survival. The first is based on a multivariable excess hazard model that includes age as covariate. The second is non-parametric and is based on the inverse probability weighting. These estimators take differently into account the informative censoring induced by the expected mortality process. The former offers great flexibility whereas the latter requires neither the assumption of a specific distribution nor a model-building strategy. Because of its simplicity and availability in commonly used software, the nonparametric estimator should be considered by cancer registries for population-based studies

Cancer net survival on registry data: use of the new unbiased Pohar-Perme estimator and magnitude of the bias with the classical methods.

Net survival, the survival which might occur if cancer was the only cause of death, is a major epidemiological indicator required for international or temporal comparisons. Recent findings have shown that all classical methods used for routine estimation of net survival from cancer-registry data, sometimes called "relative-survival methods," provide biased estimates. Meanwhile, an unbiased estimator, the Pohar-Perme estimator (PPE), was recently proposed. Using real data, we investigated the magnitude of the errors made by four "relative-survival" methods (Ederer I, Hakulinen, Ederer II and a univariable regression model) vs. PPE as reference and examined the influence of time of follow-up, cancer prognosis, and age on the errors made. The data concerned seven cancer sites (2,51,316 cases) collected by FRANCIM cancer registries. Net survivals were estimated at 5, 10 and 15 years postdiagnosis. At 5 years, the errors were generally small. At 10 years, in good-prognosis cancers, the errors made in nonstandardized estimates with all classical methods were generally great (+2.7 to +9% points in prostate cancer) and increased in age-class estimations (vs. 5-year ones). At 15 years, in bad- or average-prognosis cancers, the errors were often substantial whatever the nature of the estimation. In good-prognosis cancers, the errors in nonstandardized estimates of all classical methods were great and sometimes very important. With all classical methods, great errors occurred in age-class estimates resulting in errors in age-standardized estimates (+0.4 to +3.2% points in breast cancer). In estimating net survival, cancer registries should abandon all classical methods and adopt the new Pohar-Perme estimator

Physical activity and lung cancer risk in men and women.

International audienceAlthough evidence has accumulated that recreational physical activities (PA) may reduce lung cancer risk, there is little evidence concerning the possible role of a potentially more important source of PA, namely occupational PA. We investigated both recreational and lifetime occupational PA in relation to lung cancer risk in a population-based case-control study in Montreal, Canada (NCASES = 727; NCONTROLS = 1,351).Unconditional logistic regression was used to estimate odds ratios (OR), separately for men and women, adjusting for smoking, exposure to occupational carcinogens, and sociodemographic and lifestyle factors.In both sexes, increasing recreational PA was associated with a lower lung cancer risk (ORMEN = 0.66, 95% confidence interval (CI) 0.47-0.92; ORWOMEN = 0.55, 95% CI 0.34-0.88, comparing the highest versus lowest tertiles). For occupational PA, no association was observed among women, while increasing occupational PA was associated with increased risk among men (ORMEN = 1.96, 95% CI 1.27-3.01). ORs were not modified by occupational lung carcinogen exposure, body mass index, and smoking level; results were similar across lung cancer histological types.Our results support the previous findings for recreational PA and lung cancer risk. Unexpectedly, our findings suggest a positive association for occupational PA; this requires replication and more detailed investigation