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With known cause of death (CoD), competing risk survival methods are applicable in estimating disease-specific survival. Relative survival analysis may be used to estimate disease-specific survival when cause of death is either unknown or subject to misspecification and not reliable for practical usage. This method is popular for population-based cancer survival studies using registry data and does not require CoD information. The standard estimator is the ratio of all-cause survival in the cancer cohort group to the known expected survival from a general reference population. Disease-specific death competes with other causes of mortality, potentially creating dependence among the CoD. The standard ratio estimate is only valid when death from disease and death from other causes are independent. To relax the independence assumption, we formulate dependence using a copula-based model. Likelihood-based parametric method is used to fit the distribution of disease-specific death without CoD information, where the copula is assumed known and the distribution of other cause of mortality is derived from the reference population. We propose a sensitivity analysis, where the analysis is conducted across a range of assumed dependence structures. We demonstrate the utility of our method through simulation studies and an application to French breast cancer data., Comment: 15 pages, 3 figures, 6 tables

The development of high-throughput sequencing and targeted therapies has led to the emergence of personalized medicine: a patient's molecular profile or the presence of a specific biomarker of drug response will correspond to a treatment recommendation made either by a physician or by a treatment assignment algorithm. The growing number of such algorithms raises the question of how to quantify their clinical impact knowing that a personalized medicine strategy will inherently include different versions of treatment. We thus specify an appropriate causal framework with multiple versions of treatment to define the causal effects of interest for precision medicine strategies and estimate them emulating clinical trials with observational data. Therefore, we determine whether the treatment assignment algorithm is more efficient than different control arms: gold standard treatment, observed treatments or random assignment of targeted treatments. Causal estimates of the precision medicine effects are first evaluated on simulated data and they demonstrate a lower biases and variances compared with naive estimation of the difference in expected outcome between treatment arms. The various simulations scenarios also point out the different bias sources depending on the clinical situation (heterogeneity of response, assignment of observed treatments etc.). A RShiny interactive application is also provided to further explore other user-defined scenarios. The method is then applied to data from patient-derived xenografts (PDX): each patient tumour is implanted in several immunodeficient cloned mice later treated with different drugs, thus providing access to all corresponding drug sensitivities for all patients. Access to these unique pre-clinical data emulating counterfactual outcomes allows to validate the reliability of causal estimates obtained with the proposed method., Comment: Around 12 pages, with 5 figures Associated GitHub repository: https://github.com/JonasBeal/Causal_Precision_Medicine

We conduct a review to assess how the simulation of repeated or recurrent events are planned. For such multivariate time-to-events, it is well established that the underlying mechanism is likely to be complex and to involve in particular both heterogeneity in the population and event-dependence. In this respect, we particularly focused on these two dimensions of events dynamic when mimicking actual data. Next, we investigate whether the processes generated in the simulation studies have similar properties to those expected in the clinical data of interest. Finally we describe a simulation scheme for generating data according to the timescale of choice (gap time/ calendar) and to whether heterogeneity and/or event-dependence are to be considered. The main finding is that event-dependence is less widely considered in simulation studies than heterogeneity. This is unfortunate since the occurrence of an event may alter the risk of occurrence of new events.

Competing risks model time to first event and type of first event. An example from hospital epidemiology is the incidence of hospital-acquired infection, which has to account for hospital discharge of non-infected patients as a competing risk. An illness-death model would allow to further study hospital outcomes of infected patients. Such a model typically relies on a Markov assumption. However, it is conceivable that the future course of an infected patient does not only depend on the time since hospital admission and current infection status but also on the time since infection. We demonstrate how a modified competing risks model can be used for nonparametric estimation of transition probabilities when the Markov assumption is violated.

The ROC curve and the corresponding AUC are popular tools for the evaluation of diagnostic tests. They have been recently extended to assess prognostic markers and predictive models. However, due to the many particularities of time-to-event outcomes, various definitions and estimators have been proposed in the literature. This review article aims at presenting the ones that accommodate to right-censoring, which is common when evaluating such prognostic markers.