A Statistical Testing Strategy Accounting for Random and Nonrandom (Skewed) X-Chromosome Inactivation Identifies Lung Cancer Susceptibility Loci among Smokers.

INTRODUCTION: Lung cancer is the most common cancer worldwide in mortality and the second in incidence. Epidemiological studies found a higher lung cancer risk for smoking women in comparison to men, but these sex differences, irrespective of smoking habits, remain controversial. One of the hypotheses concerns the genetic contribution of the sex chromosomes. However, while genome-wide association studies identified many lung cancer susceptibility loci, these analyses have excluded X-linked loci. METHODS: To account for nongenetic factors, we first presented an association test based on an additive-multiplicative hazard model accounting for random/nonrandom X-inactivation process. A simulation study was performed to investigate the properties of the proposed test as compared with the Wald test from a Cox model with random X-inactivation process and the partial likelihood ratio test proposed by Xu et al. accounting for nonrandom X-inactivation process. Then, we performed an X chromosome-wide association study on 9,261 individuals from the population-based cohort CARTaGENE to identify susceptibility loci for lung cancer among current and past smokers. We adjusted for the PLCOm2012 lung cancer risk score used in screening programs. RESULTS: Simulation results show the good behavior of the proposed test in terms of power and type I error probability as compared to the Xu et al. and the Wald test. Using the proposed test statistic and adjusting for the PLCOm2012 score, the X chromosome-wide statistical analysis identified two SNPs in low-linkage disequilibrium located in the IL1RAPL1 (IL-1 R accessory protein-like) gene: rs12558491 (p = 2.75×10-9) and rs12835699 (p = 1.26×10-6). For both SNPs, the minor allele was associated with lower lung cancer risk. Adjusting for multiple testing, no signal was detected using the Wald or the Xu et al. likelihood ratio tests. CONCLUSION: By taking into account smoking behavior and the X-inactivation process, the investigation of the X chromosome has shed a new light on the association between X-linked loci and lung cancer. We identified two loci associated with lung cancer located in the IL1RAPL1 gene. This finding would have been overlooked by examining only results from other test statistics.

Analyzing cohort studies with interval-censored data: A new model-based linear rank-type test.

To compare two or more survival distributions with interval-censored data, various nonparametric tests have been proposed. Some are based on the G ρ $$ {G}^{\rho } $$ -family introduced by Harrington and Fleming (1991) that allows flexibility for situations in which the hazard ratio decreases monotonically to unity. However, it is unclear how to choose the appropriate value of the parameter ρ $$ \rho $$ . In this work, we propose a novel linear rank-type test for analyzing interval-censored data that derived from a proportional reversed hazard model. We show its relationship with decreasing hazard ratio. This test statistic provides an alternative to the G ρ $$ {G}^{\rho } $$ -based test statistics by bypassing the choice of the ρ $$ \rho $$ parameter. Simulation results show its good behavior. Two studies on breast cancer and drug users illustrate its practical uses and highlight findings that would have been overlooked if other tests had been used. The test is easy to implement with standard software and can be used for a wide range of situations with interval-censored data to test the equality of survival distributions between two or more independent groups.

Epidemiological characteristics of the COVID-19 spring outbreak in Quebec, Canada: a population-based study.

BACKGROUND: By mid-July 2020, more than 108,000 COVID-19 cases had been diagnosed in Canada with more than half in the province of Quebec. In this context, we launched a study to analyze the epidemiological characteristics and the socio-economic impact of the spring outbreak in the population. METHOD: We conducted an online survey of the participants of the CARTaGENE population-based cohort, composed of middle-aged and older adults. We collected information on socio-demographic, lifestyle, health condition, COVID-19 related symptoms and COVID-19 testing. We studied the association between these factors and two outcomes: the status of having been tested for SARS-CoV-2 and the status of having received a positive test. These associations were measured with univariate and multivariate analyses using a hybrid tree-based regression model. RESULTS: Among the 8,129 respondents from the CARTaGENE cohort, 649 were tested for COVID-19 and 41 were positive. Medical workers and individuals having a contact with a COVID-19 patient had the highest probabilities of being tested (32% and 42.4%, respectively) and of being positive (17.2% and 13.0%, respectively) among those tested. Approximately 8% of the participants declared that they have experienced at least one of the four COVID-19 related symptoms chosen by the Public Health authorities (fever, cough, dyspnea, anosmia) but were not tested. Results from the tree-based model analyses adjusted on exposure factors showed that the combination of dyspnea, dry cough and fever was highly associated with being tested whereas anosmia, fever, and headache were the most discriminant factors for having a positive test among those tested. During the spring outbreak, more than one third of the participants have experienced a decrease in access to health services. There were gender and age differences in the socio-economic and emotional impacts of the pandemic. CONCLUSION: We have shown some discrepancies between the symptoms associated with being tested and being positive. In particular, the anosmia is a major discriminant symptom for positivity whereas ear-nose-throat symptoms seem not to be COVID-19 related. The results also emphasize the need of increasing the accessibility of testing for the general population.

Evaluation of the accuracy of the PLCOm2012 6-year lung cancer risk prediction model among smokers in the CARTaGENE population-based cohort.

BACKGROUND: The PLCOm2012 prediction tool for risk of lung cancer has been proposed for a pilot program for lung cancer screening in Quebec, but has not been validated in this population. We sought to validate PLCOm2012 in a cohort of Quebec residents, and to determine the hypothetical performance of different screening strategies. METHODS: We included smokers without a history of lung cancer from the population-based CARTaGENE cohort. To assess PLCOm2012 calibration and discrimination, we determined the ratio of expected to observed number of cases, as well as the sensitivity, specificity and positive predictive values of different risk thresholds. To assess the performance of screening strategies if applied between Jan. 1, 1998, and Dec. 31, 2015, we tested different thresholds of the PLCOm2012 detection of lung cancer over 6 years (1.51%, 1.70% and 2.00%), the criteria of Quebec's pilot program (for people aged 55-74 yr and 50-74 yr) and recommendations from 2021 United States and 2016 Canada guidelines. We assessed shift and serial scenarios of screening, whereby eligibility was assessed annually or every 6 years, respectively. RESULTS: Among 11 652 participants, 176 (1.51%) lung cancers were diagnosed in 6 years. The PLCOm2012 tool underestimated the number of cases (expected-to-observed ratio 0.68, 95% confidence interval [CI] 0.59-0.79), but the discrimination was good (C-statistic 0.727, 95% CI 0.679-0.770). From a threshold of 1.51% to 2.00%, sensitivities ranged from 52.3% (95% CI 44.6%-59.8%) to 44.9% (95% CI 37.4%-52.6%), specificities ranged from 81.6% (95% CI 80.8%-82.3%) to 87.7% (95% CI 87.0%-88.3%) and positive predictive values ranged from 4.2% (95% CI 3.4%-5.1%) to 5.3% (95% CI 4.2%-6.5%). Overall, 8938 participants had sufficient data to test performance of screening strategies. If eligibility was estimated annually, Quebec pilot criteria would have detected fewer cancers than PLCOm2012 at a 2.00% threshold (48.3% v. 50.2%) for a similar number of scans per detected cancer. If eligibility was estimated every 6 years, up to 26 fewer lung cancers would have been detected; however, this scenario led to higher positive predictive values (highest for PLCOm2012 with a 2.00% threshold at 6.0%, 95% CI 4.8%-7.3%). INTERPRETATION: In a cohort of Quebec smokers, the PLCOm2012 risk prediction tool had good discrimination in detecting lung cancer, but it may be helpful to adjust the intercept to improve calibration. The implementation of risk prediction models in some of the provinces of Canada should be done with caution.

Socio-Demographic Factors Associated With COVID-19 Vaccine Hesitancy Among Middle-Aged Adults During the Quebec's Vaccination Campaign.

Introduction: The objective of this study was to characterize the combinations of demographic and socioeconomic characteristics associated to the unwillingness to receive the COVID-19 vaccines during the 2021 Quebec's vaccination campaign. Materials and Methods: In March-June 2021, we conducted an online survey of the participants of the CARTaGENE population-based cohort, composed of middle-aged and older adults. After comparing the vaccinated and unvaccinated participants, we investigated vaccine hesitancy among participants who were unvaccinated. For identifying homogeneous groups of individuals with respect to vaccine hesitancy, we used a machine learning approach based on a hybrid tree-based model. Results: Among the 6,105 participants of the vaccine cohort, 3,553 (58.2%) had at least one dose of COVID-19 vaccine. Among the 2,552 participants, 221 (8.7%) did not want to be vaccinated (91) or were uncertain (130). The median age for the unvaccinated participants was 59.3 years [IQR 54.7-63.9]. The optimal hybrid tree-based model identified seven groups. Individuals having a household income lower than $100,000 and being born outside of Canada had the highest rate of vaccine hesitancy (28% [95% CI 19.8-36.3]). For those born in Canada, the vaccine hesitancy rate among the individuals who have a household income below $50,000 before the pandemic or are Non-retired was of 12.1% [95% CI 8.7-15.5] and 10.6% [95% CI 7.6-13.7], respectively. For the participants with a high household income before the pandemic (more than $100,000) and a low level of education, those who experienced a loss of income during the pandemic had a high level of hesitancy (19.2% [8.5-29.9]) whereas others who did not experience a loss of income had a lower level of hesitancy (6.0% [2.8-9.2]). For the other groups, the level of hesitancy was low of around 3% (3.2% [95% CI 1.9-4.4] and 3.4% [95% CI 1.5-5.2]). Discussion: Public health initiatives to tackle vaccine hesitancy should take into account these socio-economic determinants and deliver personalized messages toward people having socio-economic difficulties and/or being part of socio-cultural minorities.

Five-year absolute risk estimates of colorectal cancer based on CCRAT model and polygenic risk scores: A validation study using the Quebec population-based cohort CARTaGENE.

The objective was to evaluate the predictive performance of the Colorectal Cancer Risk Assessment Tool (CCRAT) and three polygenic risk scores (Hsu et al., 2015; Law et al., 2019, Archambault et al., 2020) to predict the occurrence of colorectal cancer at five years in a Quebec population-based cohort. By using the CARTaGENE cohort, we computed the absolute risk of colorectal cancer with the CCRAT model, the polygenic risk scores (PRS) and combined clinico-genetic models (CCRAT + PRS). We also tailored the CCRAT model by using the marginal age-specific colorectal incidence rates in Canada and the risk score distribution. We reported the calibration and the discrimination. Performances of the PRSs, combined and tailored CCRAT models were compared to the original CCRAT model. The expected-to-observed ratio of the original CCRAT model was 0.54 [0.43-0.68]. The c-index was 74.79 [68.3-80.5]. The tailored CCRAT model improved the expected-to-observed ratio (0.74 [0.59-0.94]) and c-index (76.39 [69.7-82.1]). All PRS improved the expected-to-observed ratios (around 0.83, confidence intervals including one). PRSs' c-indexes were not significantly different from CCRAT models. Results from the combined models were close to those from the PRS models, Archambault combined model's c-index being significantly higher than the original and tailored CCRAT models (78.67 [70.8-86.5]; p < 0.001 and p = 0.028, respectively). In this Quebec cohort, CCRAT model has a good discrimination with a poor calibration. While the tailored CCRAT provides some gain in calibration, clinico-genetic models improved both calibration and discrimination. However, better calibrations must be obtained before a practical use among the inhabitants of Quebec province.

Validation of breast cancer risk assessment tools on a French-Canadian population-based cohort.

OBJECTIVES: Evaluate the accuracy of the Breast Cancer Risk Assessment Tool (BCRAT), International Breast Cancer Intervention Study risk evaluation tool (IBIS), Polygenic Risk Scores (PRS) and combined scores (BCRAT+PRS and IBIS +PRS) to predict the occurrence of invasive breast cancers at 5 years in a French-Canadian population. DESIGN: Population-based cohort study. SETTING: We used the population-based cohort CARTaGENE, composed of 43 037 Quebec residents aged between 40 and 69 years and broadly representative of the population recorded on the Quebec administrative health insurance registries. PARTICIPANTS: 10 200 women recruited in 2009-2010 were included for validating BCRAT and IBIS and 4555 with genetic information for validating the PRS and combined scores. OUTCOME MEASURES: We computed the absolute risks of breast cancer at 5 years using BCRAT, IBIS, four published PRS and combined models. We reported the overall calibration performance, goodness-of-fit test and discriminatory accuracy. RESULTS: 131 (1.28%) women developed a breast cancer at 5 years for validating BCRAT and IBIS and 58 (1.27%) for validating PRS and combined scores. Median follow-up was 5 years. BCRAT and IBIS had an overall expected-to-observed ratio of 1.01 (0.85-1.19) and 1.02 (0.86-1.21) but with significant differences when partitioning by risk groups (p<0.05). IBIS' c-index was significantly higher than BCRAT (63.42 (59.35-67.49) vs 58.63 (54.05-63.21), p=0.013). PRS scores had a global calibration around 0.82, with a CI including one, and non-significant goodness-of-fit tests. PRS' c-indexes were non-significantly higher than BCRAT and IBIS, the highest being 64.43 (58.23-70.63). Combined models did not improve the results. CONCLUSIONS: In this French-Canadian population-based cohort, BCRAT and IBIS have good mean calibration that could be improved for risk subgroups, and modest discriminatory accuracy. Despite this modest discriminatory power, these tools can be of interest for primary care physicians for delivering a personalised message to their high-risk patients, regarding screening and lifestyle counselling.

Spatiotemporal trends and prognosis of end-stage renal disease patients with biopsy-proven immunoglobulin A nephropathy in France from 2010 to 2014.

BACKGROUND: Although end-stage renal disease (ESRD) is frequently used as an outcome marker for primary immunoglobulin A nephropathy (IgAN), the clinical course after reaching ESRD is not well documented. This study examined patients' characteristics and survival in ESRD-related biopsy-proven IgAN in France. METHODS: French Renal Epidemiology and Information Network Registry data from 2010 to 2014 were used to analyse patients' survival and outcome in incident ESRD patients >16 years of age with biopsy-proven primary IgAN, in comparison with other primary and secondary glomerulonephritis (GN), adult polycystic kidney disease (ADPKD) or diabetes. Multivariable survival analysis was adjusted for age, sex, time on dialysis and comorbidities. RESULTS: Among 17 138 incident dialysis patients with ESRD, IgAN (242.8/10 000 dialysis initiation) represents the most common GN related to ESRD during 2010. IgAN patients were the youngest, and had the fewest comorbidities and the highest use of peritoneal dialysis (PD) (17%). In comparison with the haemodialysis group, hazard ratios for death were not different in the preemptive transplantation group [0.46, 95% confidence interval (CI) 0.17-1.28] and in the PD group (0.77, 95% CI 0.44-1.33). Mortality rates in IgAN patients with preemptive transplantation and in those receiving dialysis waiting for transplantation were 2.9% (95% CI 0.0-5.6) and 6.7% (95% CI 0.9-12.3). Mortality rates of ADPKD patients receiving dialysis waiting for transplantation were higher (18%, 95% CI 3.1-30.6). CONCLUSION: IgAN has the best prognosis among primary and secondary GN. IgAN patients receiving dialysis waiting transplantation seem to have a more favourable prognosis than ADPKD patients, who usually comprise the reference population. The underlying reasons for the difference in access treatment modalities should be investigated to improve survival with respect to renal disease.

Erratum: Spatiotemporal trends and prognosis of end stage renal disease patients with biopsy-proven IgA nephropathy in France, 2010-2014.

[This corrects the article DOI: 10.1093/ckj/sfaa029.][This corrects the article DOI: 10.1093/ckj/sfaa029.].

Quantifying the Predictive Accuracy of a Polygenic Risk Score for Predicting Incident Cancer Cases : Application to the CARTaGENE Cohort.

With the increasing use of polygenic risk scores (PRS) there is a need for adapted methods to evaluate the predictivity of these tools. In this work, we propose a new pseudo-R 2 criterion to evaluate PRS predictive accuracy for time-to-event data. This new criterion is related to the score statistic derived under a two-component mixture model. It evaluates the effect of the PRS on both the propensity to experience the event and on the dynamic of the event among the susceptible subjects. Simulation results show that our index has good properties. We compared our index to other implemented pseudo-R 2 for survival data. Along with our index, two other indices have comparable good behavior when the PRS has a non-null propensity effect, and our index is the only one to detect when the PRS has only a dynamic effect. We evaluated the 5-year predictivity of an 18-single-nucleotide-polymorphism PRS for incident breast cancer cases on the CARTaGENE cohort using several pseudo-R 2 indices. We report that our index, which summarizes both a propensity and a dynamic effect, had the highest predictive accuracy. In conclusion, our proposed pseudo-R 2 is easy to implement and well suited to evaluate PRS for predicting incident events in cohort studies.

Percutaneous Ablation Versus Robotic Partial Nephrectomy in the Treatment of cT1b Renal Tumors: Oncologic and Functional Outcomes of a Propensity Score-weighted Analysis.

INTRODUCTION: The purpose of this study was to assess oncologic and functional outcomes of both percutaneous ablation (cryoablation and radiofrequency ablation) and robot-assisted partial nephrectomy (RAPN) in the treatment of renal tumors larger than 4 cm. MATERIALS AND METHODS: We retrospectively analyzed prospectively collected data from 102 consecutive patients, who underwent minimally invasive treatment for cT1b renal tumors at our institution. Primary renal function outcome was assessed by estimated glomerular filtration rate preservation at baseline and 1 year postoperatively. Perioperative data and functional and oncologic outcome were collected. Multivariate regression models were used to compare functional outcomes between groups. Cancer-specific survival and recurrence-free survival were estimated at 2 years using the Kaplan-Meier method and compared with Cox proportional hazards regression model to calculate hazard ratios (HRs). To control for selection bias between the different treatments, we adjusted our models with an inverse probability of treatment weighting propensity score. RESULTS: There was no significant difference in renal preservation between the groups (P = .664). Multivariate analysis did not show a statistically significant difference in terms of renal function outcomes between the RAPN and percutaneous thermal ablation groups. The adjusted HR regarding the local recurrence-free survival was significantly shorter for the cryoablation group (HR, 4.3; 95% confidence interval, 1.78-10.37; P = .001). CONCLUSIONS: Our study demonstrated the equivalence between RAPN and percutaneous ablative techniques for the preservation of renal function in the treatment of T1b tumors. RAPN offers a better local control than percutaneous ablation, in terms of primary success rate.

The Need of an Open Data Quality Policy: The Case of the "Transparency - Health" Database in the Prevention of Conflict of Interest.

Open data available largely and with minimal constraints to the general public and journalists are needed to help rebuild trust between citizens and the health system. By opening data, we can expect to increase the democratic accountability, the self-empowerment of citizens. This article aims at assessing the quality and reusability of the Transparency - Health database with regards to the FAIR principles. More specifically, we observe the quality of the identity of the French medical doctors in the Transp-db. This study shows that the quality of the data in the Transp-db does not allow to identity with certainty those who benefit from an advantage or remuneration to be confirmed, reducing noticeably the impact of the open data effort.