SmoothHazard:An R package for fitting regression models to interval-censored observations of illness-death models

The irreversible illness-death model describes the pathway from an initial state to an absorbing state either directly or through an intermediate state. This model is frequently used in medical applications where the intermediate state represents illness and the absorbing state represents death. In many studies, disease onset times are not known exactly. This happens for example if the disease status of a patient can only be assessed at follow-up visits. In this situation the disease onset times are interval-censored. This article presents the SmoothHazard package for R. It implements algorithms for simultaneously fitting regression models to the three transition intensities of an illness-death model where the transition times to the intermediate state may be interval-censored and all the event times can be right-censored. The package parses the individual data structure of the subjects in a data set to find the individual contributions to the likelihood. The three baseline transition intensity functions are modelled by Weibull distributions or alternatively by M -splines in a semi-parametric approach. For a given set of covariates, the estimated transition intensities can be combined into predictions of cumulative event probabilities and life expectancies

Intérêts des méthodes utilisées dans les études populationnelles pour estimer la survie nette dans les essais cliniques

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Correcting for misclassification and selection effects in estimating net survival in clinical trials

BackgroundNet survival, a measure of the survival where the patients would only die from the cancer under study, may be compared between treatment groups using either “cause-specific methods”, when the causes of death are known and accurate, or “population-based methods”, when the causes are missing or inaccurate. The latter methods rely on the assumption that mortality due to other causes than cancer is the same as the expected mortality in the general population with same demographic characteristics derived from population life tables. This assumption may not hold in clinical trials where patients are likely to be quite different from the general population due to some criteria for patient selection.MethodsIn this work, we propose and assess the performance of a new flexible population-based model to estimate long-term net survival in clinical trials and that allows for cause-of-death misclassification and for effects of selection. Comparisons were made with cause-specific and other population-based methods in a simulation study and in an application to prostate cancer clinical trial data.ResultsIn estimating net survival, cause-specific methods seemed to introduce important biases associated with the degree of misclassification of cancer deaths. The usual population-based method provides also biased estimates, depending on the strength of the selection effect. Compared to these methods, the new model was able to provide more accurate estimates of net survival in long-term clinical trials.ConclusionFinally, the new model paves the way for new methodological developments in the field of net survival methods in multicenter clinical trials

Analyse de données de survie en présence de censure par intervalles : le package SmoothHazard

Analyse de données de survie en présence de censure par intervalles : le package SmoothHazar

Analyse de données de survie en présence de censure par intervalles : le package SmoothHazard

Analyse de données de survie en présence de censure par intervalles : le package SmoothHazar

When a joint model should be preferred over a linear mixed model for analysis of longitudinal health-related quality of life data in cancer clinical trials

International audienceBackground: Patient-reported outcomes such as health-related quality of life (HRQoL) are increasingly used as endpoints in randomized cancer clinical trials. However, the patients often drop out so that observation of the HRQoL longitudinal outcome ends prematurely, leading to monotone missing data. The patients may drop out for various reasons including occurrence of toxicities, disease progression, or may die. In case of informative dropout, the usual linear mixed model analysis will produce biased estimates. Unbiased estimates cannot be obtained unless the dropout is jointly modeled with the longitudinal outcome, for instance by using a joint model composed of a linear mixed (sub)model linked to a survival (sub)model. Our objective was to investigate in a clinical trial context the consequences of using the most frequently used linear mixed model, the random intercept and slope model, rather than its corresponding joint model.Methods: We first illustrate and compare the models on data of patients with metastatic pancreatic cancer. We then perform a more formal comparison through a simulation study.Results: From the application, we derived hypotheses on the situations in which biases arise and on their nature. Through the simulation study, we confirmed and complemented these hypotheses and provided general explanations of the bias mechanisms.Conclusions In particular, this article reveals how the linear mixed model fails in the typical situation where poor HRQoL is associated with an increased risk of dropout and the experimental treatment improves survival. Unlike the joint model, in this situation the linear mixed model will overestimate the HRQoL in both arms, but not equally, misestimating the difference between the HRQoL trajectories of the two arms to the disadvantage of the experimental arm

Joint modelling with competing risks of dropout for longitudinal analysis of health-related quality of life in cancer clinical trials

International audiencePurpose: Health-related quality of life (HRQoL) is an important endpoint in cancer clinical trials. Analysis of HRQoL longitudinal data is plagued by missing data, notably due to dropout. Joint models are increasingly receiving attention for modelling longitudinal outcomes and the time-to-dropout. However, dropout can be informative or non-informative depending on the cause.Methods We propose using a joint model that includes a competing risks sub-model for the cause-specific time-to-dropout. We compared a competing risks joint model (CR JM) that distinguishes between two causes of dropout with a standard joint model (SJM) that treats all the dropouts equally. First, we applied the CR JM and SJM to data from 267 patients with advanced oesophageal cancer from the randomized clinical trial PRODIGE 5/ACCORD 17 to analyse HRQoL data in the presence of dropouts unrelated and related to a clinical event. Then, we compared the models using a simulation study.Results We showed that the CR JM performed as well as the SJM in situations where the risk of dropout was the same whatever the cause. In the presence of both informative and non-informative dropouts, only the SJM estimations were biased, impacting the HRQoL estimated parameters Conclusion The systematic collection of the reasons for dropout in clinical trials would facilitate the use of CR JMs, which could be a satisfactory approach to analysing HRQoL data in presence of both informative and non-informative dropout.Trial registration: This study is registered with ClinicalTrials.gov, number NCT00861094

Handling informative dropout in longitudinal analysis of health-related quality of life: application of three approaches to data from the esophageal cancer clinical trial PRODIGE 5/ACCORD 17

International audienceAbstract Background Health-related quality of life (HRQoL) has become a major endpoint to assess the clinical benefit of new therapeutic strategies in oncology clinical trials. Typically, HRQoL outcomes are analyzed using linear mixed models (LMMs). However, longitudinal analysis of HRQoL in the presence of missing data remains complex and unstandardized. Our objective was to compare the modeling alternatives that account for informative dropout. Methods We investigated three alternative methods—the selection model (SM), pattern-mixture model (PMM), and shared-parameters model (SPM)—in relation to the LMM. We first compared them on the basis of methodological arguments highlighting their advantages and drawbacks. Then, we applied them to data from a randomized clinical trial that included 267 patients with advanced esophageal cancer for the analysis of four HRQoL dimensions evaluated using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire. Results We highlighted differences in terms of outputs, interpretation, and underlying modeling assumptions; this methodological comparison could guide the choice of method according to the context. In the application, none of the four models detected a significant difference between the two treatment arms. The estimated effect of time on HRQoL varied according to the method: for all analyzed dimensions, the PMM estimated an effect that contrasted with those estimated by the SM and SPM; the LMM estimated effects were confirmed by the SM (on two of four HRQoL dimensions) and SPM (on three of four HRQoL dimensions). Conclusions The PMM, SM, or SPM should be used to confirm or invalidate the results of LMM analysis when informative dropout is suspected. Of these three alternative methods, the SPM appears to be the most interesting from both theoretical and practical viewpoints. Trial registration This study is registered with ClinicalTrials.gov , number NCT00861094

Distribution- and anchor-based methods to determine the minimally important difference on patient-reported outcome questionnaires in oncology: a structured review

Abstract Background Interpretation of differences or changes in patient-reported outcome scores should not only consider statistical significance, but also clinical relevance. Accordingly, accurate determination of the minimally important difference (MID) is crucial to assess the effectiveness of health care interventions, as well as for sample size calculation. Several methods have been proposed to determine the MID. Our aim was to review the statistical methods used to determine MID in patient-reported outcome (PRO) questionnaires in cancer patients, focusing on the distribution- and anchor-based approaches and to present the variability of criteria used as well as possible limitations. Methods We performed a systematic search using PubMed. We searched for all cancer studies related to MID determination on a PRO questionnaire. Two reviewers independently screened titles and abstracts to identify relevant articles. Data were extracted from eligible articles using a predefined data collection form. Discrepancies were resolved by discussion and the involvement of a third reviewer. Results Sixty-three articles were identified, of which 46 were retained for final analysis. Both distribution- and anchor-based approaches were used to assess the MID in 37 studies (80.4%). Different time points were used to apply the distribution-based method and the most frequently reported distribution was the 0.5 standard deviation at baseline. A change in a PRO external scale (N = 13, 30.2%) and performance status (N = 15, 34.9%) were the most frequently used anchors. The stability of the MID over time was rarely investigated and only 28.2% of studies used at least 3 assessment timepoints. The robustness of anchor-based MID was questionable in 37.2% of the studies where the minimal number of patients by anchor category was less than 20. Conclusion Efforts are needed to improve the quality of the methodology used for MID determination in PRO questionnaires used in oncology. In particular, increased attention to the sample size should be paid to guarantee reliable results. This could increase the use of these specific thresholds in future studies