Multidimensional penalized splines for survival models: illustration for net survival trend analyses.

BACKGROUND: In descriptive epidemiology, there are strong similarities between incidence and survival analyses. Because of the success of multidimensional penalized splines (MPSs) in incidence analysis, we propose in this pedagogical paper to show that MPSs are also very suitable for survival or net survival studies. METHODS: The use of MPSs is illustrated in cancer epidemiology in the context of survival trends studies that require specific statistical modelling. We focus on two examples (cervical and colon cancers) using survival data from the French cancer registries (cases 1990-2015). The dynamic of the excess mortality hazard according to time since diagnosis was modelled using an MPS of time since diagnosis, age at diagnosis and year of diagnosis. Multidimensional splines bring the flexibility necessary to capture any trend patterns while penalization ensures selecting only the complexities necessary to describe the data. RESULTS: For cervical cancer, the dynamic of the excess mortality hazard changed with the year of diagnosis in opposite ways according to age: this led to a net survival that improved in young women and worsened in older women. For colon cancer, regardless of age, excess mortality decreases with the year of diagnosis but this only concerns mortality at the start of follow-up. CONCLUSIONS: MPSs make it possible to describe the dynamic of the mortality hazard and how this dynamic changes with the year of diagnosis, or more generally with any covariates of interest: this gives essential epidemiological insights for interpreting results. We use the R package survPen to do this type of analysis.

An Overview of Regression Models for Adverse Events Analysis.

Over the last few years, several review articles described the adverse events analysis as sub-optimal in clinical trials. Indeed, the context surrounding adverse events analyses often imply an overwhelming number of events, a lack of power to find associations, but also a lack of specific training regarding those complex data. In randomized controlled trials or in observational studies, comparing the occurrence of adverse events according to a covariable of interest (e.g., treatment) is a recurrent question in the analysis of drug safety data, and adjusting other important factors is often relevant. This article is an overview of the existing regression models that may be considered to compare adverse events and to discuss model choice regarding the characteristics of the adverse events of interest. Many dimensions may be relevant to compare the adverse events between patients, (e.g., timing, recurrence, and severity). Recent efforts have been made to cover all of them. For chronic treatments, the occurrence of intercurrent events during the patient follow-up usually needs the modeling approach to be adapted (at least with regard to their interpretation). Moreover, analysis based on regression models should not be limited to the estimation of relative effects. Indeed, absolute risks stemming from the model should be presented systematically to help the interpretation, to validate the model, and to encourage comparison of studies.

Improved 30-Day Survival Estimation in ICU Patients: A Comparative Analysis of Different Approaches With Real-World Data.

OBJECTIVES: The objective of this study was to compare three different approaches for estimating 30-day survival in ICU studies, considering the issue of informative censoring that occurs when patients are lost to follow-up after discharge. DESIGN: A comparative analysis was conducted to evaluate the effect of different approaches on the estimation of 30-day survival. Three methods were compared: the classical approach using the Kaplan-Meier (KM) estimator and Cox regression modeling, the competing risk approach using the Fine and gray model, considering censoring as a competing event, and the logistic regression approach. SETTING: The study was conducted in a university ICU and data from patients admitted between 2010 and 2020 were included. Patient characteristics were collected from electronic records. PATIENTS: A total of 10,581 patients were included in the study. The true date of death for each patient, obtained from a national registry, allowed for an absence of censoring. INTERVENTIONS: All patients were censored at the time of discharge from the ICU, and the three different approaches were applied to estimate the mortality rate and the effects of covariates on mortality. Regression analyses were performed using five variables known to be associated with ICU mortality. MEASUREMENTS AND MAIN RESULTS: The 30-day survival rate for the included patients was found to be 80.5% (95% CI, 79.7-81.2%). The KM estimator severely underestimated the 30-day survival (50.6%; 95% CI, 48.0-53.4%), while the competing risk and logistic regression approaches provided similar results, only slightly overestimating the survival rate (84.5%; 95% CI, 83.8-85.2%). Regression analyses showed that the estimates were not systematically biased, with the Cox and logistic regression models exhibiting greater bias compared with the competing risk regression method. CONCLUSIONS: The competing risk approach provides more accurate estimates of 30-day survival and is less biased compared with the other methods evaluated.

Comparison of 2 Methods for Estimating Multiple Sclerosis-Related Mortality.

BACKGROUND AND OBJECTIVES: Determining whether multiple sclerosis (MS) causes death is challenging. Our objective was to contrast 2 frameworks to estimate probabilities of death attributed to MS (PMS) and other causes (Pother): the cause-specific framework (CSF), which requires the causes of death, and the excess mortality framework (EMF), which does not. METHODS: We used data from the Observatoire Français de la Sclérose en Plaques (OFSEP, n = 37,524) and from a comparative subset where causes of death were available (4,004 women with relapsing-onset MS [R-MS]). In CSF, the probabilities were estimated using the Aalen-Johansen method. In EMF, they were estimated from the excess mortality hazard, which is the additional mortality among patients with MS as compared with the expected mortality in the matched general population. PMS values were estimated at 30 years of follow-up, (1) with both frameworks in the comparative subset, by age group at onset, and (2) with EMF only in the OFSEP population, by initial phenotype, sex, and age at onset. RESULTS: In the comparative subset, the estimated 30-year PMS values were greater using EMF than CSF: 10.9% (95% CI 8.3-13.6) vs 8.7% (6.4-11.8) among the youngest and 20.4% (11.3-29.5) vs 16.2% (8.7-30.2) for the oldest groups, respectively. In the CSF, probabilities of death from unknown causes ranged from 1.5% (0.7-3.0) to 6.4% (2.5-16.4), and even after their reallocation, PMS values remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the 2 frameworks, and the estimated POther (EMF vs CSF) was 2.6% (2.5-2.6) vs 2.1% (1.2-3.9) and 18.1% (16.9-19.3) vs 26.4% (16.5-42.2), respectively, for the youngest and oldest groups. In the OFSEP population, the estimated 30-year PMS values ranged from 7.5% (6.4-8.7) to 24.0% (19.1-28.9) in patients with R-MS and from 25.4% (21.1-29.7) to 36.8% (28.3-45.3) in primary progressive patients, depending on sex and age. DISCUSSION: EMF has the great advantage of not requiring death certificates, their quality being less than optimal. Conceptually, it also seems more relevant because it avoids having to state, for each individual, whether death was directly or indirectly caused by MS or whether it would have occurred anyway, which is especially difficult in such chronic diseases.

Monitoring multidimensional aspects of quality of life after cancer immunotherapy: protocol for the international multicentre, observational QUALITOP cohort study.

INTRODUCTION: Immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy, have significantly improved the clinical outcomes of various malignancies. However, they also cause immune-related adverse events (irAEs) that can be challenging to predict, prevent and treat. Although they likely interact with health-related quality of life (HRQoL), most existing evidence on this topic has come from clinical trials with eligibility criteria that may not accurately reflect real-world settings. The QUALITOP project will study HRQoL in relation to irAEs and its determinants in a real-world study of patients treated with immunotherapy. METHODS AND ANALYSIS: This international, observational, multicentre study takes place in France, the Netherlands, Portugal and Spain. We aim to include about 1800 adult patients with cancer treated with immunotherapy in a specifically recruited prospective cohort, and to additionally obtain data from historical real-world databases (ie, databiobanks) and medical administrative registries (ie, national cancer registries) in which relevant data regarding other adult patients with cancer treated with immunotherapy has already been stored. In the prospective cohort, clinical health status, HRQoL and psychosocial well-being will be monitored until 18 months after treatment initiation through questionnaires (at baseline and 3, 6, 12 and 18 months thereafter), and by data extraction from electronic patient files. Using advanced statistical methods, including causal inference methods, artificial intelligence algorithms and simulation modelling, we will use data from the QUALITOP cohort to improve the understanding of the complex relationships among treatment regimens, patient characteristics, irAEs and HRQoL. ETHICS AND DISSEMINATION: All aspects of the QUALITOP project will be conducted in accordance with the Declaration of Helsinki and with ethical approval from a suitable local ethics committee, and all patients will provide signed informed consent. In addition to standard dissemination efforts in the scientific literature, the data and outcomes will contribute to a smart digital platform and medical data lake. These will (1) help increase knowledge about the impact of immunotherapy, (2) facilitate improved interactions between patients, clinicians and the general population and (3) contribute to personalised medicine. TRIAL REGISTRATION NUMBER: NCT05626764.

Is the Social Gradient in Net Survival Observed in France the Result of Inequalities in Cancer-Specific Mortality or Inequalities in General Mortality?

BACKGROUND: In cancer net survival analyses, if life tables (LT) are not stratified based on socio-demographic characteristics, then the social gradient in mortality in the general population is ignored. Consequently, the social gradient estimated on cancer-related excess mortality might be inaccurate. We aimed to evaluate whether the social gradient in cancer net survival observed in France could be attributable to inaccurate LT. METHODS: Deprivation-specific LT were simulated, applying the social gradient in the background mortality due to external sources to the original French LT. Cancer registries' data from a previous French study were re-analyzed using the simulated LT. Deprivation was assessed according to the European Deprivation Index (EDI). Net survival was estimated by the Pohar-Perme method and flexible excess mortality hazard models by using multidimensional penalized splines. RESULTS: A reduction in net survival among patients living in the most-deprived areas was attenuated with simulated LT, but trends in the social gradient remained, except for prostate cancer, for which the social gradient reversed. Flexible modelling additionally showed a loss of effect of EDI upon the excess mortality hazard of esophagus, bladder and kidney cancers in men and bladder cancer in women using simulated LT. CONCLUSIONS: For most cancers the results were similar using simulated LT. However, inconsistent results, particularly for prostate cancer, highlight the need for deprivation-specific LT in order to produce accurate results.

FGF19 and muscle architecture in older patients.

BACKGROUND: Sarcopenia has a significant medical and economic impact. Serum fibroblast growth factor 19 (FGF19) has recently been described as promoting muscle mass and strength, and could be an interesting marker for early diagnosis of sarcopenia and prevention of its consequences. Ultrasound is a robust non-invasive technique used to measure muscle parameters, which cannot be evaluated by usual body composition measures, but are known to be associated with muscle function. In this cross-sectional cohort study, we aimed to determine whether FGF19 levels were correlated with functional muscle tests and muscle ultrasound parameters. METHODS: Patients over 70 years old with a mobility disability risk were recruited from the cohort of the "well on your feet" mobility loss prevention program. Sarcopenia was diagnosed according to the European Working Group on Sarcopenia in Older Patients 2 (EWGSOP2) criteria. We have performed functional battery tests, muscle ultrasound measures and bioimpedance spectroscopy. FGF19 levels were measured by the ELISA method. RESULTS: Out of 52 patients involved (34 women, mean age 81.3 years), 30 patients were sarcopenic (15 patients with probable sarcopenia and 15 with certain sarcopenia). Sarcopenic patients were older (mean 82.8 versus 79.6 years, P = 0.033), with higher frailty Fried score (P = 0.006), lower IADL score (P = 0.008), had lower daily protein intakes (P = 0.023) and were less performant to muscle functional tests than non-sarcopenic patients. Serum FGF19 levels were negatively correlated with the SPPB score (rs = 0.28; P = 0.045). FGF19 levels were correlated positively with the pennation angle (rs = 0.31; P = 0.024), but negatively with muscle fiber length (rs = -0.44; P = 0.001). We found no association between FGF19 and muscle thickness (P = 0.243). CONCLUSION: We highlighted in older patients significant correlations between FGF19 levels, pennation angle and muscle fiber length, suggesting that FGF19 could provide an enabling environment for the development of large muscle fibers, as previously suggested in histological studies in mice. However, high FGF-19 levels were unexpectedly associated with a low SPPB score. Further studies are needed to validate and further elucidate these exploratory findings.

Mortality and Associated Causes in Hemophagocytic Lymphohistiocytosis: A Multiple-Cause-of-Death Analysis in France.

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome with an overall mortality rate of 40%. A multiple-cause-of-death analysis allows for the characterization of mortality and associated causes over an extended period. Death certificates, collected between 2000 and 2016 by the French Epidemiological Centre for the Medical Causes of Death (CepiDC, Inserm), containing the ICD10 codes for HLH (D76.1/2), were used to calculate HLH-related mortality rates and to compare them with the general population (observed/expected ratios, O/E). HLH was mentioned in 2072 death certificates as the underlying cause of death (UCD, n = 232) or as a non-underlying cause of death (NUCD, n = 1840). The mean age at death was 62.4 years. The age-standardized mortality rate was 1.93/million person-years and increased over the study period. When HLH was an NUCD, the most frequently associated UCDs were hematological diseases (42%), infections (39.4%), and solid tumors (10.4%). As compared to the general population, HLH decedents were more likely to have associated CMV infections or hematological diseases. The increase in mean age at death over the study period indicates progress in diagnostic and therapeutic management. This study suggests that the prognosis of HLH may be at least partially related to coexisting infections and hematological malignancies (either as causes of HLH or as complications).

Clinical characteristics and outcome of 318 families with familial monoclonal gammopathy: A multicenter Intergroupe Francophone du Myélome study.

Familial forms of monoclonal gammopathy, defined as multiple myeloma (MM) or Monoclonal Gammopathy of Undetermined Significance (MGUS), are relatively infrequent and most series reported in the literature describe a limited number of families. MM rarely occurs in a familial context. MGUS is observed much more commonly, which can in some cases evolve toward full-blown MM. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of MM, the pathogenesis of familial MM remains largely unexplained. In order to identify genetic factors predisposing to familial monoclonal gammopathy, the Intergroupe Francophone du Myélome identified 318 families with at least two confirmed cases of monoclonal gammopathy. There were 169 families with parent/child pairs and 164 families with cases in at least two siblings, compatible with an autosomal transmission. These familial cases were compared with sporadic cases who were matched for age at diagnosis, sex and immunoglobulin isotype, with 10 sporadic cases for each familial case. The gender distribution, age and immunoglobulin subtypes of familial cases were unremarkable in comparison to sporadic cases. With a median follow-up of 7.4 years after diagnosis, the percentage of MGUS cases having evolved to MM was 3%. The median overall survival of the 148 familial MM cases was longer than that of matched sporadic cases, with projected values of 7.6 and 16.1 years in patients older and younger than 65 years, respectively. These data suggest that familial cases of monoclonal gammopathy are similar to sporadic cases in terms of clinical presentation and carry a better prognosis.

Effects of socioeconomic status on excess mortality in patients with multiple sclerosis in France: A retrospective observational cohort study.

Background: The effects of socio-economic status on mortality in patients with multiple sclerosis is not well known. The objective was to examine mortality due to multiple sclerosis according to socio-economic status. Methods: A retrospective observational cohort design was used with recruitment from 18 French multiple sclerosis expert centers participating in the Observatoire Français de la Sclérose en Plaques. All patients lived in metropolitan France and had a definite or probable diagnosis of multiple sclerosis according to either Poser or McDonald criteria with an onset of disease between 1960 and 2015. Initial phenotype was either relapsing-onset or primary progressive onset. Vital status was updated on January 1st 2016. Socio-economic status was measured by an ecological index, the European Deprivation Index and was attributed to each patient according to their home address. Excess death rates were studied according to socio-economic status using additive excess hazard models with multidimensional penalised splines. The initial hypothesis was a potential socio-economic gradient in excess mortality. Findings: A total of 34,169 multiple sclerosis patients were included (88% relapsing onset (n = 30,083), 12% progressive onset (n = 4086)), female/male sex ratio 2.7 for relapsing-onset and 1.3 for progressive-onset). Mean age at disease onset was 31.6 (SD = 9.8) for relapsing-onset and 42.7 (SD = 10.8) for progressive-onset. At the end of follow-up, 1849 patients had died (4.4% for relapsing-onset (n = 1311) and 13.2% for progressive-onset (n = 538)). A socio-economic gradient was found for relapsing-onset patients; more deprived patients had a greater excess death rate. At thirty years of disease duration and a year of onset of symptoms of 1980, survival probability difference (or deprivation gap) between less deprived relapsing-onset patients (EDI = -6) and more deprived relapsing-onset patients (EDI = 12) was 16.6% (95% confidence interval (CI) [10.3%-22.9%]) for men and 12.3% (95%CI [7.6%-17.0%]) for women. No clear socio-economic mortality gradient was found in progressive-onset patients. Interpretation: Socio-economic status was associated with mortality due to multiple sclerosis in relapsing-onset patients. Improvements in overall care of more socio-economically deprived patients with multiple sclerosis could help reduce these socio-economic inequalities in multiple sclerosis-related mortality. Funding: This study was funded by the ARSEP foundation "Fondation pour l'aide à la recherche sur la Sclérose en Plaques" (Grant Reference Number 1122). Data collection has been supported by a grant provided by the French State and handled by the "Agence Nationale de la Recherche," within the framework of the "Investments for the Future" programme, under the reference ANR-10-COHO-002, Observatoire Français de la Sclérose en Plaques (OFSEP).

Protocol for a prospective quasi-experimental study on SARS-CoV-2 transmission during outdoor sports events in France: the COVID-ESO project.

INTRODUCTION: The spread of SARS-CoV-2 and its variants in the community remains a major concern despite the application of control measures including the banning of mass sporting events. The circulation of SARS-CoV-2 within the general population, and potentially within the population practicing outdoor sports activities, suggests contexts conducive to the transmission of the virus. We hypothesise that outdoor sports events (OSEs) do not present a higher risk of SARS-CoV-2 contamination. The objective of the COVID-ESO project is to measure if individuals participating in OSE present a similar risk of SARS-CoV-2 transmission compared with individuals not participating in OSE, in France. METHODS AND ANALYSIS: The COVID-ESO project is a prospective, quasi-experimental study to be conducted in volunteer individuals likely to participate in OSE. Six events are targeted across France to be included. Three sport trials will be eligible for the study: running, cycling and triathlon. Each individual participating in the OSE will choose one of his or her usual training partner to be eligible for the unexposed control group. Individuals will be matched (1:1) on age, sex and the district of residence. Individuals assigned to the exposed group will participate in the OSE, whereas individuals assigned to the unexposed group will not participate in the OSE. All individuals will be asked to perform saliva tests on the day of the event and 7 days after the event. A questionnaire including sociodemographic, clinical and exposure data to SARS-CoV-2 will be sent by email for both groups on the day before the event and 7 days after the event. Differences in SARS-CoV-2 infection rates between the exposed versus the unexposed group will be analysed by fitting a conditional logistic regression model, adjusted for potential confounders. As the sport events unfold, data will be analyzed by performing sequential meta-analyses. ETHICS AND DISSEMINATION: This protocol has been approved by the ethical committee. Ethical approval has been obtained for the Clinical research and committee of South West of France, 10 June 2021. COMITE DE PROTECTION DES PERSONNES DU SUD-OUEST ET OUTRE-MER 4 under the reference number 21.03.23.71737/CPP2021-04-045 a COVID/2021-A00845-36. Findings generated from this study will be shared to national health and sport authorities.

Mortality associated with Behçet's disease in France assessed by multiple-cause-of-death analysis.

OBJECTIVES: To examine the mortality rates and causes of death among French decedents with Behçet's disease (BD). METHODS: Data collected between 1979 and 2016 by the French Epidemiological Center for the Medical Causes of Death was used to calculate BD-related mortality rates and examine differences according to age and sex, determine underlying and non-underlying causes of death (UCD/NUCD), and compare with the general population (observed/expected ratios, O/E). RESULTS: A total of 328 death certificates mentioned BD as UCD (n = 171) or NUCD (n = 157). The mean (± SD) age at death was 52.8 (± 11.3) years in men and 58.4 (± 16.5) in women (vs. 71.2 and 79.8 in the general population, respectively). The age-standardized mortality rate was 0.15/million person-years and significantly increased over the study period (p < 0.01). When BD was the UCD, the most frequent associated causes were infections (25.1%), underlying organ dysfunction (21.6%), and arterial events (15.2%). As compared to the general population, BD decedents < 45 years were more likely to die from a cardiovascular event (O/E = 6.25, p < 0.001); decedents > 45 years were more likely to die from infection (O/E = 9.69, p < 0.001). Between 1979 and 2016, BD as UCD decreases whereas NUCD increased. CONCLUSION: This study found an earlier mean age at death for BD compared to the general population; young patients were more prone to die from cardiovascular complication whereas older patients died more frequently from infections. Over the years, the mean age at death increased and BD was less frequently considered as an UCD, suggesting a better knowledge of the disease and complications. Key Points • Patients with Behçet's disease die earlier than the general population. • Young patients were more prone to die from cardiovascular complication. • Older patients died more frequently from infections.

How do age and social environment affect the dynamics of death hazard and survival in patients with breast or gynecological cancer in France?

Several studies have investigated the association between net survival (NS) and social inequalities in people with cancer, highlighting a varying influence of deprivation depending on the type of cancer studied. However, few of these studies have accounted for the effect of social inequalities over the follow-up period, and/or according to the age of the patients. Thus, using recent and more relevant statistical models, we investigated the effect of social environment on NS in women with breast or gynecological cancer in France. The data were derived from population-based cancer registries, and women diagnosed with breast or gynecological cancer between 2006 and 2009 were included. We used the European deprivation index (EDI), an aggregated index, to define the social environment of the women included. Multidimensional penalized splines were used to model excess mortality hazard. We observed a significant effect of the EDI on NS in women with breast cancer throughout the follow-up period, and especially at 1.5 years of follow-up in women with cervical cancer. Regarding corpus uteri and ovarian cancer patients, the effect of deprivation on NS was less pronounced. These results highlight the impact of social environment on NS in women with breast or gynecological cancer in France thanks to a relevant statistical approach, and identify the follow-up periods during which the social environment may have a particular influence. These findings could help investigate targeted actions for each cancer type, particularly in the most deprived areas, at the time of diagnosis and during follow-up.

Outcomes and survival of a modern dual mobility cup and uncemented collared stem in displaced femoral neck fractures at a minimum 5-year follow-up.

INTRODUCTION: The choice of implant type for total hip replacement in the treatment of femoral neck fractures remains debated. Some authors advocate for the systematic use of cemented stems, while others do not use dual mobility first-line. We therefore conducted a retrospective study using a dual mobility cup (DMC) and an uncemented collared stem (UCS) in order to: (1) confirm the low dislocation rate in this indication, (2) assess other surgical complications, in particular periprosthetic fractures, (3) ensure that these benefits are maintained over time, at a minimum follow-up of 5 years and, (4) assess the rate of revision of the implants. HYPOTHESIS: Our hypothesis was that the dual mobility dislocation rate for the treatment of femoral neck fractures was lower than for bipolar hemiarthroplasties or single mobility hip prostheses. PATIENTS AND METHODS: A retrospective study of 244 femoral neck fractures (242 patients) treated with DMC and UCS was conducted, between 2013 and 2014. The mean age was 83±10 years (60-104). The occurrence of dislocation, periprosthetic fracture, infection of the surgical site, loosening, reoperation and revision were investigated. The HOOS Joint Replacement (JR) score was collected. The cumulative incidence with mortality was used as a competing risk. RESULTS: The mean follow-up was 6 years±0.5 (5-7). At the last follow-up, 108 patients (50%) had died. Twenty-three patients (9.5%) were lost to follow-up. One case of symptomatic aseptic loosening of DMC was observed. The cumulative incidence of dislocations and periprosthetic fractures at 5 years were 2% (95% CI: 0.9-5.4) and 3% (95% CI: 1.2-6), respectively. The 5-year cumulative incidence of surgical site infections was 3.5% (95% CI: 1.8-7). The cumulative incidence of reoperations at 5 years was 7% (95% CI: 4.5-11). The causes of reoperation were periprosthetic fracture (n=6), infection (n=8), postoperative hematoma (n=2) and cup malposition (n=2). The cumulative incidence of a revision at 5 years was 2.7% (95% CI: 1.2-6). The cumulative incidence of a surgical complication from any cause at 5 years was 9% (95% CI: 6.7-14.8). The mean HOOS JR score was 79±5 (52-92). DISCUSSION: The cumulative incidence of dislocation at 5 years is low and other surgical complications (including periprosthetic fractures) do not increase during this period for DMC associated with UCS, in femoral neck fractures. The use of this type of implant is reliable in the treatment of femoral neck fractures. LEVEL OF EVIDENCE: IV; retrospective study without control group.

Socioeconomic Environment and Survival in Patients with Digestive Cancers: A French Population-Based Study.

Social inequalities are an important prognostic factor in cancer survival, but little is known regarding digestive cancers specifically. We aimed to provide in-depth analysis of the contextual social disparities in net survival of patients with digestive cancer in France, using population-based data and relevant modeling. Digestive cancers (n = 54,507) diagnosed between 2006-2009, collected through the French network of cancer registries, were included (end of follow-up 30 June 2013). Social environment was assessed by the European Deprivation Index. Multidimensional penalized splines were used to model excess mortality hazard. We found that net survival was significantly worse for individuals living in a more deprived environment as compared to those living in a less deprived one for esophageal, liver, pancreatic, colon and rectal cancers, and for stomach and bile duct cancers among females. Excess mortality hazard was up to 57% higher among females living in the most deprived areas (vs. least deprived) at 1 year of follow-up for bile duct cancer, and up to 21% higher among males living in the most deprived areas (vs. least deprived) regarding colon cancer. To conclude, we provide a better understanding of how the (contextual) social gradient in survival is constructed, offering new perspectives for tackling social inequalities in digestive cancer survival.

Still's Disease Mortality Trends in France, 1979-2016: A Multiple-Cause-of-Death Study.

Still's disease (SD) is often considered a benign disease, with low mortality rates. However, few studies have investigated SD mortality and its causes and most of these have been single-center cohort studies. We sought to examine mortality rates and causes of death among French decedents with SD. We performed a multiple-cause-of-death analysis on data collected between 1979 and 2016 by the French Epidemiological Center for the Medical Causes of Death. SD-related mortality rates were calculated and compared with the general population (observed/expected ratios, O/E). A total of 289 death certificates mentioned SD as the underlying cause of death (UCD) (n = 154) or as a non-underlying causes of death (NUCD) (n = 135). Over the study period, the mean age at death was 55.3 years (vs. 75.5 years in the general population), with differences depending on the period analyzed. The age-standardized mortality rate was 0.13/million person-years and was not different between men and women. When SD was the UCD, the most frequent associated causes were cardiovascular diseases (n = 29, 18.8%), infections (n = 25, 16.2%), and blood disorders (n = 11, 7.1%), including six cases (54%) with macrophage activation syndrome. As compared to the general population, SD decedents aged <45 years were more likely to die from a cardiovascular event (O/E = 3.41, p < 0.01); decedents at all ages were more likely to die from infection (O/E = 7.96-13.02, p < 0.001).

Integrating a Prevention Care Path into the Daily Life of Older Adults with Mobility Disability Risk: Introducing a Predictive Response Model to Exercise.

INTRODUCTION: Exercise and nutrition are the best targets to tackle mobility issues in community-dwelling older adults. As exercise response relies on multiple factors, improving the understanding of their interactions is a necessity to tailor effective preventive strategies. Based on a prevention care path designed for community-dwelling older adults with mobility disability risk, our main goal was to determine the predictive factors of the response to a multimodal intervention, combining structured exercise training and nutritional counselling. Thus, this study aimed to tailor prevention programs for non-responder participants. METHODS: We analyzed the response of participants to a prevention program and built a multivariate predictive model to highlight the profile of the best responders. The model was based on the likelihood of at least 1 point of short physical performance battery (SPPB) score gain. Inclusion criteria were being aged ≥70 years and having completed a multicomponent group-based supervised training consisting of 20 sessions (10 weeks). RESULTS: A total of 103 participants were included, their mean ± SD age was 81.9 ± 5.7 years. The model demonstrated interactions between baseline SPPB score (OR=0.42; p < 0.001), body mass index (BMI; OR=0.82; p=0.003), and grip strength value (OR=1.15; p=0.008). The highest probability of response was found for participants with low SPPB, normal BMI (21 kg/m2), and high grip strength (27 kg). CONCLUSION: This study demonstrated that the response to a multimodal intervention in community-dwelling older adults with mobility disability risk was influenced by the baseline SPPB score, BMI, and grip strength value. To increase the proportion of responders, strategies that could be more effective include constituting more homogenous group, and implementing a specific approach for obese sarcopenic older adults and those with low grip strength by increasing the dose of physical activity and monitoring endurance and mobility activities between sessions. Our results provide important consideration for the development of targeted-interventions.

Effects of Age and Disease Duration on Excess Mortality in Patients With Multiple Sclerosis From a French Nationwide Cohort.

OBJECTIVE: To determine the effects of current age and disease duration on excess mortality in multiple sclerosis (MS), we describe the dynamics of excess death rates over these 2 time scales and study the effect of age at MS clinical onset on these dynamics, separately in each initial phenotype. METHODS: We used data from 18 French MS expert centers participating in the Observatoire Français de la Sclérose en Plaques. Patients with MS living in metropolitan France and having a clinical onset between 1960 and 2014 were included. Vital status was updated on January 1, 2016. For each MS phenotype separately (relapsing onset [RMS] or primary progressive [PPMS]), we used an innovative statistical method to model the logarithm of excess death rates by a multidimensional penalized spline of age and disease duration. RESULTS: Among 37,524 patients (71% women, mean age at MS onset ± SD 33.0 ± 10.6 years), 2,883 (7.7%) deaths were observed and 7.8% of patients were lost to follow-up. For patients with RMS, there was no excess mortality during the first 10 years after disease onset; afterwards, whatever the age at onset, excess death rates increased with current age. From current age 70, the excess death rate values converged and became identical whatever the age at disease onset, which means that disease duration had no more effect. Excess death rates were higher in men, with an excess hazard ratio of 1.46 (95% confidence interval 1.25-1.70). In contrast, in patients with PPMS, excess death rates rapidly increased from disease onset, and were associated with age at onset, but not with sex. CONCLUSIONS: In RMS, current age has a stronger effect on MS mortality than disease duration, while their respective effects are not clear in PPMS.

Association Between Short-, Intermediate-, and Long-term Mortality and Myocardial Injury After Noncardiac Surgery After Hip Fracture Surgery: A Retrospective Cohort.

BACKGROUND: For more than 20 years, hip fracture 1-year mortality has remained around 20%. An elevation of the postoperative troponin peak within 72 hours (myocardial injury after noncardiac surgery [MINS]) is associated with a greater risk of short-term mortality in the general population. However, there seem to be conflicting results in the specific population who undergo hip fracture surgery, with some studies finding an association between troponin and mortality and some not. The objective of the present study was to investigate the association of MINS and the short- (before 28th day), intermediate- (before 180th day), and long-term (before 365th day) mortality after hip fracture surgery. METHODS: We conducted a single-center retrospective cohort of patients undergoing hip fracture surgery from November 2013 to December 2015. MINS was defined as postoperative troponin peak within the 72 hours >5 ng/L. Four MINS subgroups were defined according to the value of troponin peak (ie, ≥5-<20, ≥20-<65, ≥65-<1000, and ≥1000 ng/L). To document the association between the different mortality terms and the troponin peak, odds ratio (OR) and adjusted OR (aOR) associated with their 95% confidence interval (CI) with the log of the scaled troponin peak within 72 hours were estimated, with and without patients presenting a postoperative acute coronary syndrome (ACS). Cox proportional hazards modeling was used to estimate hazard ratio (HR) and adjusted HR (aHR) of death between the no MINS and MINS subgroups. The adjustment was performed on the main confounding factors (ie, sex, American Society of Anesthesiologists [ASA] physical status, dementia status, age, and time from admission to surgery). RESULTS: Among 729 participants, the mean age was 83.1 (standard deviation [SD] = 10.8) years, and 77.4% were women; 30 patients presented an ACS (4%). Short-, intermediate-, and long-term mortality were at 5%, 16%, and 23%, respectively. The troponin peak was significantly associated with all terms of mortality before and after adjustment and before and after exclusion of patients presenting an ACS. HR and aHR for each subgroup of troponin level were significantly associated with an increased probability of survival, except for the 5 to 20 ng/L group for which aHR was not significant (1.75, 95% CI, 0.82-3.74). In the landmark analysis, there was still an association between survival at the 365th day and troponin peak after the short- and intermediate-term truncated mortality. CONCLUSIONS: MINS is associated with short-, intermediate-, and long-term mortality after hip fracture surgery. This could be a valuable indicator to determine the population at high risk of mortality that could benefit from targeted prevention and possible intervention.

Multidimensional penalized splines for incidence and mortality-trend analyses and validation of national cancer-incidence estimates.

BACKGROUND: Cancer-incidence and mortality-trend analyses require appropriate statistical modelling. In countries without a nationwide cancer registry, an additional issue is estimating national incidence from local-registry data. The objectives of this study were to (i) promote the use of multidimensional penalized splines (MPS) for trend analyses; (ii) estimate the national cancer-incidence trends, using MPS, from only local-registry data; and (iii) propose a validation process of these estimates. METHODS: We used an MPS model of age and year for trend analyses in France over 1990-2015 with a projection up to 2018. Validation was performed for 22 cancer sites and relied essentially on comparison with reference estimates that used the incidence/health-care ratio over the period 2011-2015. Alternative estimates that used the incidence/mortality ratio were also used to validate the trends. RESULTS: In the validation assessment, the relative differences of the incidence estimates (2011-2015) with the reference estimates were <5% except for testis cancer in men and < 7% except for larynx cancer in women. Trends could be correctly derived since 1990 despite incomplete histories in some registries. The proposed method was applied to estimate the incidence and mortality trends of female lung cancer and prostate cancer in France. CONCLUSIONS: The validation process confirmed the validity of the national French estimates; it may be applied in other countries to help in choosing the most appropriate national estimation method according to country-specific contexts. MPS form a powerful statistical tool for trend analyses; they allow trends to vary smoothly with age and are suitable for modelling simple as well as complex trends thanks to penalization. Detailed trend analyses of lung and prostate cancers illustrated the suitability of MPS and the epidemiological interest of such analyses.