Data-Driven Simulations to Assess the Impact of Study Imperfections in Time-to-Event Analyses.

Quantitative bias analysis (QBA) permits assessment of the expected impact of various imperfections of the available data on the results and conclusions of a particular real-world study. This article extends QBA methodology to multivariable time-to-event analyses with right-censored endpoints, possibly including time-varying exposures or covariates. The proposed approach employs data-driven simulations, which preserve important features of the data at hand while offering flexibility in controlling the parameters and assumptions that may affect the results. First, the steps required to perform data-driven simulations are described, and then two examples of real-world time-to-event analyses illustrate their implementation and the insights they may offer. The first example focuses on the omission of an important time-invariant predictor of the outcome in a prognostic study of cancer mortality, and permits separating the expected impact of confounding bias from non-collapsibility. The second example assesses how imprecise timing of an interval-censored event - ascertained only at sparse times of clinic visits - affects its estimated association with a time-varying drug exposure. The simulation results also provide a basis for comparing the performance of two alternative strategies for imputing the unknown event times in this setting. The R scripts that permit the reproduction of our examples are provided.

Recipient age influences survival after liver transplant: Results of the French national cohort 2007-2017.

BACKGROUND: In recent years, age at liver transplantation (LT) has markedly increased. In the context of organ shortage, we investigated the impact of recipient age on post-transplantation mortality. METHODS: All adult patients who received a first LT between 2007 and 2017 were included in this cross-sectional study. Recipients' characteristics at the time of listing, donor and surgery data, post-operative complications and follow-up of vital status were retrieved from the national transplantation database. The impact of age on 5-year overall mortality post-LT was estimated using a flexible multivariable parametric model which was also used to estimate the association between age and 10-year net survival, accounting for expected age- and sex-related mortality. RESULTS: Among the 7610 patients, 21.4% were aged 60-65 years, and 15.7% over 65. With increasing age, comorbidities increased but severity of liver disease decreased. Older recipient age was associated with decreased observed survival at 5 years after LT (p < .001), with a significant effect particularly during the first 2 years. The linear increase in the risk of death associated with age does not allow any definition of an age's threshold for LT (p = .832). Other covariates associated with an increased risk of 5-year death were dialysis and mechanical ventilation at transplant, transfusion during LT, hepatocellular carcinoma and donor age. Ten-year flexible net survival analysis confirmed these results. CONCLUSION: Although there was a selection process for older recipients, increasing age at LT was associated with an increased risk of death, particularly in the first years after LT.

Immunosuppression and cancer risk in kidney transplant recipients: A retrospective cohort study.

We assessed whether contemporary immunosuppression agents were associated with cancer among kidney transplant recipients (KTR), and if this association varied by age and sex. We studied a retrospective province-wide cohort of primary KTR (1997-2016). Employing multivariable Cox models, we estimated associations of cumulative doses of prednisone, mycophenolate and tacrolimus administered over the past 10 years, lagged by 2 years, with the incidence of primary malignant neoplasms (PMN). We assessed interactions with age and sex. To assess the impact of exposure recency, we used weighted cumulative exposure (WCE) modeling. Among 1064 KTR, 108 (10.2%) developed PMN over median follow-up of 73 months (interquartile range: 32-120). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of 0.96 (0.64-1.43), 1.34 (0.96-1.86), and 1.06 (0.88-1.29) were estimated for cumulative daily doses of prednisone (5 mg), mycophenolate (1000 mg), and tacrolimus (2 mg) administered continuously over the past 10 years, respectively. PMN risk associated with cumulative tacrolimus exposure was modified by age (interaction p = .035) and was more pronounced in 15-year and 30-year-old KTR (aHRs of 1.57 [1.08-2.28] and 1.31 [1.03-1.66], respectively) in comparison to older KTR. PMN risk increase associated with higher cumulative mycophenolate dose was more pronounced in females (aHR = 1.86 [1.15-3.00]) than in males (aHR = 1.16 [0.74-1.81]; interaction p = .131). WCE analyses suggested increased PMN risk the higher the mycophenolate doses taken 5-10 years ago. A trend toward increased PMN risk with long-term mycophenolate exposure, particularly in females, and more pronounced risk with long-term tacrolimus exposure in younger KTR, identify opportunities for tailored immunosuppression to mitigate cancer risk.

Childhood body fatness and the risk of epithelial ovarian cancer: A population-based case-control study in Montreal, Canada.

OBJECTIVE: To assess the association between childhood body fatness and epithelial ovarian cancer (EOC), and whether this association differs by type of EOC. METHODS: Using data from a population-based case-control study (497 cases and 902 controls) in Montreal, Canada conducted 2011-2016, we examined the association between childhood body fatness and EOC, overall and separately for invasive vs. borderline EOCs. A figure rating scale was used to measure body fatness at ages 5 and 10. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Quantitative bias analyses were conducted to assess the impact of exposure misclassification and non-participation. RESULTS: The aOR (95% CI) of overall EOC for high vs. low body fatness was 1.07 (0.85-1.34) at age 5 and 1.28 (0.98-1.68) at age 10. The associations were stronger for invasive EOC, specifically the endometrioid histological type. For borderline cancers, the aORs were below the null value with wide confidence intervals. Bias analyses did not reveal a strong influence of non-participation. Non-differential exposure misclassification may have biased aORs towards the null for invasive cancers but did not appear to have an appreciable influence on the aORs for borderline cancers. CONCLUSIONS: Childhood body fatness may be a risk factor for invasive EOC in later adult life. Our study highlights the potential importance of examining early life factors for a comprehensive understanding of EOC development.

Importance of accounting for timing of time-varying exposures in association studies: Hydrochlorothiazide and non-melanoma skin cancer.

PURPOSE: Hydrochlorothiazide (HCTZ), a widely prescribed antihypertensive drug with photosensitising properties, has been linked with non-melanoma skin cancer (NMSC) risk. However, previous analyses did not fully explore if and how the impact of past HCTZ exposures accumulates with prolonged use and/or depends on time elapsed since exposures. Therefore, we used different models to more comprehensively assess how NMSC risk vary with HCTZ exposure, and explore how the results may depend on modeling strategies. METHODS: We used different parametric models with alternative time-varying exposure metrics, and the flexible weighted cumulative exposure model (WCE) to estimate associations between HCTZ exposures and NMSC risk in a population-based cohort of HCTZ users over 65 years old, in the province of Ontario, Canada. RESULTS: Among 3844 HCTZ users, 273 developed NMSC during up to 8 years of follow-up. In parametric models, based on all exposures, increased duration of past HCTZ use was associated with an increase of NMSC risk but cumulative dose showed no systematic association. Yet, WCE results suggested that only exposures taken 2.5-4 years in the past were associated with the current NMSC hazard. This finding led us to re-define the parametric models, which also confirmed that any HCTZ dose taken outside this time-window were not systematically associated with NMSC incidence. CONCLUSIONS: Our analyses illustrate how flexible modeling may yield new insights into complex temporal relationships between a time-varying drug exposure and risks of adverse events. Duration and recency of antihypertensive agents exposures must be taken into account in evaluating risk and benefits.

Skin Cancer and Hydrochlorothiazide: Novel Population-Based Analyses Considering Personal Risk Factors Including Race/Ethnicity.

BACKGROUND: Hydrochlorothiazide, a common antihypertensive, has photosensitive properties, potentially increasing skin cancer risk. We evaluated melanoma and nonmelanoma skin cancer among hydrochlorothiazide users with 3 different cohorts as each allows assessment of different potential cofounders/effect modifiers, including race/ethnicity. METHODS: We built 3 cohorts using IBM MarketScan Research Databases: Commercial and Encounters (>3.5 million individuals, 2010-2018), a subcohort with health risk assessment respondents (415, 330), and Medicaid (509, 767, 2011-2017). Adults (aged 18+ years) entered the respective cohort with a first-filled prescription (cohort entry) for hydrochlorothiazide (the exposure of interest) or angiotensin-converting enzyme (ACE) inhibitors (the active comparator), with ≥12 months of continuous enrollment with medical/pharmacy coverage at baseline. We excluded those who used hydrochlorothiazide/ACE inhibitor (including fixed-dose combination products) 12 months before cohort entry and those with prior skin cancer, HIV, or organ transplant. We compared the risk for hydrochlorothiazide versus ACE inhibitor using multivariate proportional hazards regression. RESULTS: Baseline characteristics were similar, aside from more Black individuals among hydrochlorothiazide users (43.3% [95% CI, 43.0%-43.6%]) than ACE inhibitor users (28.1% [95% CI, 27.9%-28.3%]). The hazard ratio (95% CI) for nonmelanoma skin cancer related to hydrochlorothiazide (versus ACE inhibitor) was 0.96 (0.91-1.00) in the Commercial cohort, 1.01 (0.77-1.32) for the health risk assessment subcohort, and 1.33 (0.77-2.29) for Medicaid. For melanoma, the respective hazard ratios were 1.07 (0.95-1.20), 0.85 (0.43-1.67), and 0.93 (0.51-1.67), respectively. CONCLUSIONS: Our evaluation using 3 different approaches, including adjustment for race/ethnicity, did not establish a clear difference between hydrochlorothiazide and ACE inhibitor in terms of skin cancer risk.

Sex Differences in the Effectiveness of Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Sacubitril-Valsartan for the Treatment of Heart Failure.

Background PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) suggested a potential benefit of sacubitril-valsartan in women with preserved ejection fraction. Among patients with heart failure previously treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), we studied whether effectiveness of treatment with sacubitril-valsartan compared with ACEI/ARB monotherapy differed between men and women for both preserved and reduced ejection fraction. Methods and Results Data were derived from the Truven Health MarketScan Databases between January 1, 2011, and December 31, 2018. We included patients with a primary diagnosis of heart failure on treatment with ACEIs, ARBs, or sacubitril-valsartan on the basis of the first prescription after diagnosis. A total of 7181 patients treated with sacubitril-valsartan, 25 408 patients using an ACEI, and 16 177 patients treated with ARBs were included. A total of 790 readmissions or deaths occurred among 7181 patients in the sacubitril-valsartan group and 11 901 events in 41 585 patients treated with an ACEI/ARB. Adjusted for covariates, the hazard ratio (HR) for treatment with sacubitril-valsartan compared with an ACEI or ARB was 0.74 (95% CI, 0.68-0.80). The protective effect of sacubitril-valsartan was evident for men and women (women: HR, 0.75 [95% CI, 0.66-0.86]; P<0.01; men: HR, 0.71 [95% CI, 0.64-0.79]; P<0.01; P interaction 0.03). A protective effect for both sexes was seen only among those with systolic dysfunction. Conclusions Treatment with sacubitril-valsartan is more effective at reducing death and admission to the hospital for heart failure compared with ACEIs/ARBs similarly among men and women with systolic dysfunction; sex differences in the effectiveness of sacubitril-valsartan in diastolic dysfunction requires further investigation.

Comparison of Different Modeling Approaches for Prescription Opioid Use and Its Association With Adverse Events.

Previous research linking opioid prescribing to adverse drug events has failed to properly account for the time-varying nature of opioid exposure. This study aimed to explore how the risk of opioid-related emergency department visits, readmissions, or deaths (composite outcome) varies with opioid dose and duration, comparing different novel modeling techniques. A prospective cohort of 1,511 hospitalized patients discharged from 2 McGill-affiliated hospitals in Montreal, 2014-2016, was followed from the first postdischarge opioid dispensation until 1 year after discharge. Marginal structural Cox proportional hazards models and their flexible extensions were used to explore the association between time-varying opioid use and the composite outcome. Weighted cumulative exposure models assessed cumulative effects of past use and explored how its impact depends on the recency of exposure. The patient mean age was 69.6 (standard deviation = 14.9) years; 57.7% were male. In marginal structural model analyses, current opioid use was associated with a 71% increase in the hazard of opioid-related adverse events (adjusted hazard ratio = 1.71, 95% confidence interval: 1.21, 2.43). The weighted cumulative exposure results suggested that the risk cumulates over the previous 50 days of opioid consumption. Flexible modeling techniques helped assess how the risk of opioid-related adverse events may be associated with time-varying opioid exposures while accounting for nonlinear relationships and the recency of past use.

Investigating the Shape and Strength of the Relationship Between Maternal Weight Gain and Gestational Age at Delivery in Twin and Singleton Pregnancies.

Both inadequate and excessive maternal weight gain are correlated with preterm delivery in singleton pregnancies, yet this relationship has not been adequately studied in twins. We investigated the relationship between time-varying maternal weight gain and gestational age at delivery in twin pregnancies and compared it with that in singletons delivered in the same study population. We used serial weight measurements abstracted from charts for twin and singleton pregnancies delivered during 1998-2013 in Pittsburgh, Pennsylvania. Our exposure was time-varying weight gain z score, calculated using gestational age-standardized and prepregnancy body mass index-stratified twin- and singleton-specific charts, and our outcome was gestational age at delivery. Our analyses used a flexible extension of the Cox proportional hazards model that allowed for nonlinear and time-dependent effects. We found a U-shaped relationship between weight gain z score and gestational age at delivery among twin pregnancies (lowest hazard of delivery observed at z score = 1.2), which we attributed to increased hazard of early preterm spontaneous delivery among pregnancies with low weight gain and increased hazard of late preterm delivery without labor among pregnancies with high weight gain. Our findings may be useful for updating provisional guidelines for maternal weight gain in twin pregnancies.

Alcohol intake and the risk of epithelial ovarian cancer.

PURPOSE: To investigate the association between alcohol intake over the lifetime and the risk of overall, borderline, and invasive ovarian cancer. METHODS: In a population-based case-control study of 495 cases and 902 controls, conducted in Montreal, Canada, average alcohol intake over the lifetime and during specific age periods were computed from a detailed assessment of the intake of beer, red wine, white wine and spirits. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between alcohol intake and ovarian cancer risk. RESULTS: For each one drink/week increment in average alcohol intake over the lifetime, the adjusted OR (95% CI) was 1.06 (1.01-1.10) for ovarian cancer overall, 1.13 (1.06-1.20) for borderline ovarian cancers and 1.02 (0.97-1.08) for invasive ovarian cancers. This pattern of association was similarly observed for alcohol intake in early (15- < 25 years), mid (25- < 40 years) and late adulthood (≥ 40 years), as well as for the intake of specific alcohol beverages over the lifetime. CONCLUSIONS: Our results support the hypothesis that a higher alcohol intake modestly increases the risk of overall ovarian cancer, and more specifically, borderline tumours.

Comparison of cohort and nested case-control designs for estimating the effect of time-varying drug exposure on the risk of adverse event in the presence of ties.

Cohort and nested case-control (NCC) designs are frequently used in pharmacoepidemiology to assess the associations of drug exposure that can vary over time with the risk of an adverse event. Although it is typically expected that estimates from NCC analyses are similar to those from the full cohort analysis, with moderate loss of precision, only few studies have actually compared their respective performance for estimating the effects of time-varying exposures (TVE). We used simulations to compare the properties of the resulting estimators of these designs for both time-invariant exposure and TVE. We varied exposure prevalence, proportion of subjects experiencing the event, hazard ratio, and control-to-case ratio and considered matching on confounders. Using both designs, we also estimated the real-world associations of time-invariant ever use of menopausal hormone therapy (MHT) at baseline and updated, time-varying MHT use with breast cancer incidence. In all simulated scenarios, the cohort-based estimates had small relative bias and greater precision than the NCC design. NCC estimates displayed bias to the null that decreased with a greater number of controls per case. This bias markedly increased with higher proportion of events. Bias was seen with Breslow's and Efron's approximations for handling tied event times but was greatly reduced with the exact method or when NCC analyses were matched on confounders. When analyzing the MHT-breast cancer association, differences between the two designs were consistent with simulated data. Once ties were taken correctly into account, NCC estimates were very similar to those of the full cohort analysis.

Investigating Associations Between Access to Rheumatology Care, Treatment, Continuous Care, and Healthcare Utilization and Costs Among Older Individuals With Rheumatoid Arthritis.

OBJECTIVE: To examine the association between rheumatologist access, early treatment, and ongoing care of older-onset rheumatoid arthritis (RA) and healthcare utilization and costs following diagnosis. METHODS: We analyzed data from a population-based inception cohort of individuals aged > 65 years with RA in Ontario, Canada, diagnosed between 2002 and 2014 with follow-up to 2019. We assessed 4 performance measures in the first 4 years following diagnosis, including access to rheumatology care, yearly follow-up, timely treatment, and ongoing treatment with a disease-modifying antirheumatic drug. We examined annual healthcare utilization, mean direct healthcare costs, and whether the performance measures were associated with costs in year 5. RESULTS: A total of 13,293 individuals met inclusion criteria. The mean age was 73.7 (SD 5.7) years and 68% were female. Total mean direct healthcare cost per individual increased annually and was CAD $13,929 in year 5. All 4 performance measures were met for 35% of individuals. In multivariable analyses, costs for not meeting access to rheumatology care and timely treatment performance measures were 20% (95% CI 8-32) and 6% (95% CI 1-12) higher, respectively, than where those measures were met. The main driver of cost savings among individuals meeting all 4 performance measures were from lower complex continuing care, home care, and long-term care costs, as well as fewer hospitalizations and emergency visits. CONCLUSION: Access to rheumatologists for RA diagnosis, timely treatment, and ongoing care are associated with lower total healthcare costs at 5 years. Investments in improving access to care may be associated with long-term health system savings.

Determinants of long-term opioid use in hospitalized patients.

BACKGROUND: Long-term opioid use is an increasingly important problem related to the ongoing opioid epidemic. The purpose of this study was to identify patient, hospitalization and system-level determinants of long term opioid therapy (LTOT) among patients recently discharged from hospital. DESIGN: To be eligible for this study, patient needed to have filled at least one opioid prescription three-months post-discharge. We retrieved data from the provincial health insurance agency to measure medical service and prescription drug use in the year prior to and after hospitalization. A multivariable Cox Proportional Hazards model was utilized to determine factors associated with time to the first LTOT occurrence, defined as time-varying cumulative opioid duration of ≥ 60 days. RESULTS: Overall, 22.4% of the 1,551 study patients were classified as LTOT, who had a mean age of 66.3 years (SD = 14.3). Having no drug copay status (adjusted hazard ratio (aHR) 1.91, 95% CI: 1.40-2.60), being a LTOT user before the index hospitalization (aHR 6.05, 95% CI: 4.22-8.68) or having history of benzodiazepine use (aHR 1.43, 95% CI: 1.12-1.83) were all associated with an increased likelihood of LTOT. Cardiothoracic surgical patients had a 40% lower LTOT risk (aHR 0.55, 95% CI: 0.31-0.96) as compared to medical patients. Initial opioid dispensation of > 90 milligram morphine equivalents (MME) was also associated with higher likelihood of LTOT (aHR 2.08, 95% CI: 1.17-3.69). CONCLUSIONS AND RELEVANCE: Several patient-level characteristics associated with an increased risk of ≥ 60 days of cumulative opioid use. The results could be used to help identify patients who are at high-risk of continuing opioids beyond guideline recommendations and inform policies to curb excessive opioid prescribing.

System-level performance measures of access to rheumatology care: a population-based retrospective study of trends over time and the impact of regional rheumatologist supply in Ontario, Canada, 2002-2019.

OBJECTIVE: To determine whether there were improvements in rheumatology care for rheumatoid arthritis (RA) between 2002 and 2019 in Ontario, Canada, and to evaluate the impact of rheumatologist regional supply on access. METHODS: We conducted a population-based retrospective study of all individuals diagnosed with RA between January 1, 2002 and December 31, 2019. Performance measures evaluated were: (i) percentage of RA patients seen by a rheumatologist within one year of diagnosis; and (ii) percentage of individuals with RA aged 66 years and older (whose prescription drugs are publicly funded) dispensed a disease modifying anti-rheumatic drug (DMARD) within 30 days after initial rheumatologist visit. Logistic regression was used to assess whether performance improved over time and whether the improvements differed by rheumatology supply, dichotomized as < 1 rheumatologist per 75,000 adults versus ≥1 per 75,000. RESULTS: Among 112,494 incident RA patients, 84% saw a rheumatologist within one year: The percentage increased over time (adjusted odds ratio (OR) 2019 vs. 2002 = 1.43, p < 0.0001) and was consistently higher in regions with higher rheumatologist supply (OR = 1.73, 95% CI 1.67-1.80). Among seniors who were seen by a rheumatologist within 1 year of their diagnosis the likelihood of timely DMARD treatment was lower among individuals residing in regions with higher rheumatologist supply (OR = 0.90 95% CI 0.83-0.97). These trends persisted after adjusting for other covariates. CONCLUSION: While access to rheumatologists and treatment improved over time, shortcomings remain, particularly for DMARD use. Patients residing in regions with higher rheumatology supply were more likely to access care but less likely to receive timely treatment.

Adapting SIMEX to correct for bias due to interval-censored outcomes in survival analysis with time-varying exposure.

Many clinical and epidemiological applications of survival analysis focus on interval-censored events that can be ascertained only at discrete times of clinic visits. This implies that the values of time-varying covariates are not correctly aligned with the true, unknown event times, inducing a bias in the estimated associations. To address this issue, we adapted the simulation-extrapolation (SIMEX) methodology, based on assessing how the estimates change with the artificially increased time between clinic visits. We propose diagnostics to choose the extrapolating function. In simulations, the SIMEX-corrected estimates reduced considerably the bias to the null and generally yielded a better bias/variance trade-off than conventional estimates. In a real-life pharmacoepidemiological application, the proposed method increased by 27% the excess hazard of the estimated association between a time-varying exposure, representing the 2-year cumulative duration of past use of a hypertensive medication, and the hazard of nonmelanoma skin cancer (interval-censored events). These simulation-based and real-life results suggest that the proposed SIMEX-based correction may help improve the accuracy of estimated associations between time-varying exposures and the hazard of interval-censored events in large cohort studies where the events are recorded only at relatively sparse times of clinic visits/assessments. However, these advantages may be less certain for smaller studies and/or weak associations.

The Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO): Comparisons between Quebec, Manitoba, Saskatchewan, and Alberta.

BACKGROUND: Given that pregnant women taking medications are excluded from clinical trials, real-world evidence is essential. We aimed to build a Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO) and compare frequency of prematurity, low-birth-weight (LBW), major malformations, multiplicity, and gestational medication use across four provinces. METHODS: CAMCCO is a collaborative research infrastructure that uses real-world data from large provincial health care databases in Canada; developed with standardized methods to similarly construct population-based pregnancy/child cohorts with longitudinal follow-up by linking administrative/hospital/birth databases. CAMCCO also includes a common repository to i) share algorithms and case definitions based on diagnostic and procedural codes for research/training purpose, and ii) download aggregate data relevant to primary care providers, researchers, and decision makers. For this study, data from Quebec (1998-2015), Manitoba (1995-2019), Saskatchewan (1996-2020), and Alberta (2005-2018) are compared (Chi-square tests, p-values), and trends are calculated using Cochran-Armitage trend tests. RESULTS: Almost two-thirds (61%) of women took medications during pregnancy, mostly antibiotics (26%), asthma drugs (8%), and antidepressants (4%). Differences in the prevalence of prematurity (5.9-6.8%), LBW (4.0-5.2%), and multiplicity (1.0-2.5%) were statistically significant between provinces (p<0.001). Frequency of major malformations increased over time in Quebec (7-11%; p<0.001), Saskatchewan (5-11%; p<0.001), and Alberta (from 7-8%; p<0.001), and decreased in Manitoba (5-3%; p<0.001). Cardiovascular and musculoskeletal malformations were the most prevalent. INTERPRETATION: Medications are often used among Canadian pregnancies but adverse pregnancy outcomes vary across provinces. Digitized health data may help researchers and care providers understand the risk-benefit ratios related to gestational medication use, as well as province-specific trends.

External Validation of the Lupus Multivariable Outcome Score for Systemic Lupus Erythematosus Trials.

OBJECTIVE: Development of new systemic lupus erythematosus (SLE) treatments requires an effective responder index. Toward this end, we have recently developed a new Lupus Multivariable Outcome Score (LuMOS) to optimize discrimination between actively treated patients and those on placebo. We now report on external validation of LuMOS in two independent clinical trials. METHODS: Validation was performed with the Illuminate data sets that evaluated tabalumab (TB) in SLE. To accommodate laboratory results assessed on different platforms, we developed a standardized LuMOS 2.0 model that uses z score transformations of biomarker values. For validation, we calculated LuMOS 2.0 scores at week 52 for all participants. Effect size (ES), with 95% confidence intervals (CIs), compared the ability of LuMOS and the SLE Responder Index-5 (SRI-5) to discriminate between outcomes in patients randomized to TB dosage and outcomes in those randomized to a placebo. RESULTS: Mean LuMOS 2.0 scores were significantly higher (P < 0.0001) for the TB groups than the placebo group, including the Illuminate-1 trial, in which the SRI-5 did not identify significant treatment effects. For both TB groups in both trials, LuMOS 2.0-based ES indicated moderately strong treatment effects (>0.4) in contrast to weak SRI-5 effects (<0.25). For monthly TB, LuMOS 2.0-based ES were 0.44 (95% CI: 0.30-0.59) and 0.54 (95% CI: 0.39-0.68) for the Illuminate-1 and Illuminate-2 trials versus corresponding SRI-5-based ES of 0.13 (95% CI: -0.02 to +0.27) and 0.15 (95% CI: 0.01-0.30). CONCLUSION: LuMOS 2.0 detected significantly greater treatment effects compared with the SRI-5 in the Illuminate trials. Additional validation of LuMOS 2.0 in trials of non-B cell-directed therapies will be necessary to document its universality as an outcome measure.

Long-term exposure to wildfires and cancer incidence in Canada: a population-based observational cohort study.

BACKGROUND: Wildfires emit many carcinogenic pollutants that contaminate air, water, terrestrial, and indoor environments. However, little is known about the relationship between exposure to wildfires and cancer risk. We aimed to assess the associations between residential exposure to wildfires and the incidence of several cancer outcomes (lung cancer, brain cancer, non-Hodgkin lymphoma, multiple myeloma, and leukaemia) in Canada. METHODS: We did a population-based observational cohort study of participants in the 1996 Canadian Census Health and Environment Cohort. The 1996 Canadian Census Health and Environment Cohort is a nationally representative sample of Canadian adults, followed up for cancer incidence and mortality from 1996 to 2015. For this analysis, we excluded participants who lived in major Canadian cities (with a population size greater than 1·5 million people), recent immigrants, and individuals younger than 25 years or 90 years of age or older at baseline. Exposures to wildfires were assigned on the basis of area burned within a 20 km or 50 km radius of residential locations and updated for annual residential mobility. Multivariable Cox proportional hazards models were used to estimate associations between exposure to wildfires and specific cancers associated with carcinogenic compounds released by wildfires, including lung and brain cancer, non-Hodgkin lymphoma, multiple myeloma, and leukaemia, adjusted for many personal and neighbourhood-level covariates. FINDINGS: Our analyses included more than 2 million people followed up for a median of 20 years, for a total of 34 million person-years. Wildfire exposure was associated with slightly increased incidence of lung cancer and brain tumours. For example, cohort members exposed to a wildfire within 50 km of residential locations in the past 10 years had a 4·9% relatively higher incidence (adjusted hazard ratio [HR] 1·049, 95% CI 1·028-1·071) of lung cancer than unexposed populations, and a 10% relatively higher incidence (adjusted HR 1·100, 1·026-1·179) of brain tumours. Similar associations were observed for the 20 km buffer size. Wildfires were not associated with haematological cancers in this study, and concentration-response trends were not readily apparent when area burned was modelled as a continuous variable. INTERPRETATION: Long-term exposure to wildfires might increase the risk of lung cancer and brain tumours. Further work is needed to develop long-term estimates of wildfire exposures that capture the complex mixture of environmental pollutants released during these events. FUNDING: Canadian Institute for Health Research and Fonds de recherche du Quebec.