Haemoglobin trajectories in chronic kidney disease and risk of major adverse cardiovascular events.

BACKGROUND: The trajectories of haemoglobin in patients with chronic kidney disease (CKD) have been poorly described. In such patients, we aimed to identify typical haemoglobin trajectory profiles and estimate their risks of major adverse cardiovascular events (MACE). METHODS: We used 5-year longitudinal data from the CKD-REIN cohort patients with moderate to severe CKD enrolled from 40 nationally representative nephrology clinics in France. A joint latent class model was used to estimate, in different classes of haemoglobin trajectory, the competing risks of (i) MACE + defined as the first event among cardiovascular death, non-fatal myocardial infarction, stroke or hospitalization for acute heart failure, (ii) initiation of kidney replacement therapy (KRT) and (iii) non-cardiovascular death. RESULTS: During the follow-up, we gathered 33 874 haemoglobin measurements from 3011 subjects (median, 10 per patient). We identified five distinct haemoglobin trajectory profiles. The predominant profile (n = 1885, 62.6%) showed an overall stable trajectory and low risks of events. The four other profiles had nonlinear declining trajectories: early strong decline (n = 257, 8.5%), late strong decline (n = 75, 2.5%), early moderate decline (n = 356, 11.8%) and late moderate decline (n = 438, 14.6%). The four profiles had different risks of MACE, while the risks of KRT and non-cardiovascular death consistently increased from the haemoglobin decline. CONCLUSION: In this study, we observed that two-thirds of patients had a stable haemoglobin trajectory and low risks of adverse events. The other third had a nonlinear trajectory declining at different rates, with increased risks of events. Better attention should be paid to dynamic changes of haemoglobin in CKD.

Trajectories of long-term exposure to PCB153 and Benzo[a]pyrene (BaP) air pollution and risk of breast cancer.

BACKGROUND: While genetic, hormonal, and lifestyle factors partially elucidate the incidence of breast cancer, emerging research has underscored the potential contribution of air pollution. Polychlorinated biphenyls (PCBs) and benzo[a]pyrene (BaP) are of particular concern due to endocrine-disrupting properties and their carcinogenetic effect. OBJECTIVE: To identify distinct long term trajectories of exposure to PCB153 and BaP, and estimate their associations with breast cancer risk. METHODS: We used data from the XENAIR case-control study, nested within the ongoing prospective French E3N cohort which enrolled 98,995 women aged 40-65 years in 1990-1991. Cases were incident cases of primary invasive breast cancer diagnosed from cohort entry to 2011. Controls were randomly selected by incidence density sampling, and individually matched to cases on delay since cohort entry, and date, age, department of residence, and menopausal status at cohort entry. Annual mean outdoor PCB153 and BaP concentrations at residential addresses from 1990 to 2011 were estimated using the CHIMERE chemistry-transport model. Latent class mixed models were used to identify profiles of exposure trajectories from cohort entry to the index date, and conditional logistic regression to estimate their association with the odds of breast cancer. RESULTS: 5058 cases and 5059 controls contributed to the analysis. Five profiles of trajectories of PCB153 exposure were identified. The class with the highest PCB153 concentrations had a 69% increased odds of breast cancer compared to the class with the lowest concentrations (95% CI 1.08, 2.64), after adjustment for education and matching factors. The association between identified BaP trajectories and breast cancer was weaker and suffered from large CI. CONCLUSIONS: Our results support an association between long term exposure to PCB153 and the risk of breast cancer, and encourage further studies to account for lifetime exposure to persistent organic pollutants.

Association of LIfestyle for BRAin health risk score (LIBRA) and genetic susceptibility with incident dementia and cognitive decline.

INTRODUCTION: Evaluating whether genetic susceptibility modifies the impact of lifestyle-related factors on dementia is critical for prevention. METHODS: We studied 5170 participants from a French cohort of older persons free of dementia at baseline and followed for up to 17 years. The LIfestyle for BRAin health risk score (LIBRA) including 12 modifiable factors was constructed at baseline (higher score indicating greater risk) and was related to both subsequent cognitive decline and dementia incidence, according to genetic susceptibility to dementia (reflected by the apolipoprotein E [APOE] ε4 allele and a genetic risk score [GRS]). RESULTS: The LIBRA was associated with higher dementia incidence, with no significant effect modification by genetics (hazard ratio for one point score = 1.09 [95% confidence interval, 1.05; 1.13]) in APOE ε4 non-carriers and = 1.15 [1.08; 1.22] in carriers; P = 0.15 for interaction). Similar findings were obtained with the GRS and with cognitive decline. DISCUSSION: Lifestyle-based prevention may be effective whatever the genetic susceptibility to dementia.

Arteriovenous access creation and hazards of hospitalization and death in patients starting hemodialysis.

BACKGROUND: Recent evidence suggests overestimation of benefits associated with arteriovenous (AV) fistula versus graft in certain populations. We assessed hazards of all-cause and cause-specific hospitalization and death associated with AV access type in patients who started hemodialysis with a catheter in France, overall and by subgroups of age, sex, and comorbidities. METHODS: From the REIN Registry, we included patients who initiated hemodialysis with a catheter from 2010 through 2018, and identified first-created fistula or graft through the French national health-administrative database. We used joint frailty models to deal with recurrent hospitalizations and potential informative censoring by death, and inverse probability weighting to account for confounding. RESULTS: From the 18 800 patients included (mean age 68 ± 15 years, 35% women), 5% underwent AV graft creation first. Weighted hazard ratio (wHR) of all-cause hospitalization associated with graft was 1.08 (95% CI 1.02 to 1.15), that of vascular access-related hospitalization was 1.43 (95% CI 1.32 to 1.55), and those of cardiovascular- and infection-related hospitalizations were 1.14 (95% CI 1.03 to 1.26) and 1.11 (95% CI 0.97 to 1.28), respectively. Results were consistent for most subgroups, except that the highest hazard of all-cause, cardiovascular-, and infection- related hospitalizations with graft was blunted in patients with comorbidities (i.e. diabetes, wHR 1.01, 95% CI 0.93 -1.10; 1.10, 95% CI 0.96 to 1.26; and 0.94, 95% CI 0.78 to 1.12, respectively). CONCLUSIONS: In patients starting hemodialysis with a catheter, AV graft creation is associated with increased hazard of vascular access-related hospitalizations compared to fistula. This may not be the case for death or other causes of hospitalization.

Association of long-term exposure to ambient air pollution with retinal neurodegeneration: the prospective Alienor study.

Chronic exposure to air pollution may have adverse effects on neurodegenerative diseases. Glaucoma, the second leading cause of blindness worldwide, is a neurodegenerative disease of the optic nerve, characterized by progressive thinning of the retinal nerve fiber layer (RNFL). We investigated the relationship of air pollution exposure with longitudinal changes of RNFL thickness in the Alienor study, a population-based cohort of residents of Bordeaux, France, aged 75 years or more. Peripapillary RNFL thickness was measured using optical coherence tomography imaging every 2 years from 2009 to 2020. Measurements were acquired and reviewed by specially trained technicians to control quality. Air pollution exposure (particulate matter ≤2.5 µm (PM2.5), black carbon (BC), nitrogen dioxide (NO2)) was estimated at the participants' geocoded residential address using land-use regression models. For each pollutant, the 10-year average of past exposure at first RNFL thickness measurement was estimated. Associations of air pollution exposure with RNFL thickness longitudinal changes were assessed using linear mixed models adjusted for potential confounders, allowing for intra-eye and intra-individual correlation (repeated measurements). The study included 683 participants with at least one RNFL thickness measurement (62% female, mean age 82 years). The average RNFL was 90 µm (SD:14.4) at baseline. Exposure to higher levels of PM2.5 and BC in the previous 10 years was significantly associated with a faster RNFL thinning during the 11-year follow-up (-0.28 µm/year (95% confidence interval (CI) [-0.44;-0.13]) and -0.26 µm/year (95% CI [-0.40;-0.12]) per interquartile range increment; p < 0.001 for both). The size of the effect was similar to one year of age in the fitted model (-0.36 µm/year). No statistically significant associations were found with NO2 in the main models. This study evidenced a strong association of chronic exposure to fine particulate matter with retinal neurodegeneration, at air pollution levels below the current recommended thresholds in Europe.

Clinical Trial Emulation by Matching Time-dependent Propensity Scores: The Example of Estimating Impact of Kidney Transplantation.

BACKGROUND: No study to our knowledge has examined the use of observational data to emulate a clinical trial whereby patients at the time of kidney transplant proposal are randomly assigned to an awaiting transplantation or transplantation group. The main methodologic issue is definition of the baseline for dialyzed patients assigned to awaiting transplantation, resulting in the inability to use common propensity score-based approaches. We aimed to use time-dependent propensity score to better appraise the benefit of transplantation. METHODS: We studied 23,231 patients included in the French registry and on a transplant waiting list from 2005 to 2016. The main outcome was time to death. By matching on time-dependent propensity score, we obtained 10,646 pairs of recipients (transplantation group) versus comparable patients remaining on dialysis (awaiting transplantation group). RESULTS: The baseline exposure, that is, pseudo-randomization, was matching time. Median follow-up time was 3.5 years. At 10 years' follow-up, the restricted mean survival time was 8.8 years [95% confidence interval (CI) = 8.7, 8.9] in the transplantation group versus 8.2 years (95% CI = 8.1, 8.3) in the awaiting transplantation group. The corresponding life expectancy gain was 6.8 months (95% CI = 5.5, 8.2), and this corresponded to one prevented death at 10 years for 13 transplantations. CONCLUSIONS: Our study has estimated the life expectancy gain due to kidney transplantation. It confirms transplantation as the best treatment for end-stage renal disease. Furthermore, we demonstrated that this simple method should also be considered for estimating marginal effects of time-dependent exposures.

Dynamic prediction models for graft failure in paediatric kidney transplantation.

BACKGROUND: Several models have been proposed to predict kidney graft failure in adult recipients but none in younger recipients. Our objective was to propose a dynamic prediction model for graft failure in young kidney transplant recipients. METHODS: We included 793 kidney transplant recipients waitlisted before the age of 18 years who received a first kidney transplantation before the age of 21 years in France in 2002-13 and survived >90 days with a functioning graft. We used a Cox model including baseline predictors only (sex, age at transplant, primary kidney disease, dialysis duration, donor type and age, human leucocyte antigen matching, cytomegalovirus serostatus, cold ischaemia time and delayed graft function) and two joint models also accounting for post-transplant estimated glomerular filtration rate (eGFR) trajectory. Predictive performances were evaluated using a cross-validated area under the curve (AUC) and R2 curves. RESULTS: When predicting the risk of graft failure from any time within the first 7 years after paediatric kidney transplantation, the predictions for the following 3 or 5 years were accurate and much better with the joint models than with the Cox model (AUC ranged from 0.83 to 0.91 for the joint models versus 0.56 to 0.64 for the Cox model). CONCLUSION: Accounting for post-transplant eGFR trajectory strongly increased the accuracy of graft failure prediction in young kidney transplant recipients.

Time-varying associations between an exposure history and a subsequent health outcome: a landmark approach to identify critical windows.

BACKGROUND: Long-term behavioral and health risk factors constitute a primary focus of research on the etiology of chronic diseases. Yet, identifying critical time-windows during which risk factors have the strongest impact on disease risk is challenging. To assess the trajectory of association of an exposure history with an outcome, the weighted cumulative exposure index (WCIE) has been proposed, with weights reflecting the relative importance of exposures at different times. However, WCIE is restricted to a complete observed error-free exposure whereas exposures are often measured with intermittent missingness and error. Moreover, it rarely explores exposure history that is very distant from the outcome as usually sought in life-course epidemiology. METHODS: We extend the WCIE methodology to (i) exposures that are intermittently measured with error, and (ii) contexts where the exposure time-window precedes the outcome time-window using a landmark approach. First, the individual exposure history up to the landmark time is estimated using a mixed model that handles missing data and error in exposure measurement, and the predicted complete error-free exposure history is derived. Then the WCIE methodology is applied to assess the trajectory of association between the predicted exposure history and the health outcome collected after the landmark time. In our context, the health outcome is a longitudinal marker analyzed using a mixed model. RESULTS: A simulation study first demonstrates the correct inference obtained with this approach. Then, applied to the Nurses' Health Study (19,415 women) to investigate the association between body mass index history (collected from midlife) and subsequent cognitive decline (evaluated after age 70), the method identified two major critical windows of association: long before the first cognitive evaluation (roughly 24 to 12 years), higher levels of BMI were associated with poorer cognition. In contrast, adjusted for the whole history, higher levels of BMI became associated with better cognition in the last years prior to the first cognitive interview, thus reflecting reverse causation (changes in exposure due to underlying disease). CONCLUSIONS: This approach, easy to implement, provides a flexible tool for studying complex dynamic relationships and identifying critical time windows while accounting for exposure measurement errors.

Long-term atmospheric exposure to PCB153 and breast cancer risk in a case-control study nested in the French E3N cohort from 1990 to 2011.

BACKGROUND: Although the genetic and hormonal risk factors of breast cancer are well identified, they cannot fully explain the occurrence of all cases. Epidemiological and experimental studies have suggested that exposure to environmental pollutants, especially those with potential estrogenic properties, as polychlorinated biphenyls (PCBs) may have a role in breast cancer development. Being the most abundantly detected in human tissues and in the environment, congener 153 (PCB153) is widely used in epidemiological studies as indicator for total PCBs exposure. OBJECTIVES: We aimed to estimate the association between cumulative atmospheric exposure to PCB153 and breast cancer risk. METHODS: We conducted a case-control study of 5222 cases and 5222 matched controls nested within the French E3N cohort from 1990 to 2011. Annual atmospheric PCB153 concentrations were simulated with the deterministic chemistry-transport model (CHIMERE) and were assigned to women using their geocoded residential history. Their cumulative PCB153 exposure was calculated for each woman from their cohort inclusion to their index date. Breast cancer odds ratios (ORs) associated with cumulative PCB153 exposure and their 95% confidence intervals (95% CIs) were estimated using multivariate conditional logistic regression models. RESULTS: Overall, our results showed a statistically significant linear increase in breast cancer risk related to cumulative atmospheric exposure to PCB153 as a continuous variable (adjusted OR = 1.19; 95% CI: 1.08-1.31, for an increment of one standard deviation among controls (55 pg/m3)). Among women who became postmenopausal during follow-up, the association remained statistically significant (adjusted OR = 1.23; 95% CI: 1.09-1.39). In analyses by hormone receptors status, the positive association remained significant only for ER-positive breast cancer (adjusted OR = 1.18; 95% CI: 1.05-1.33). DISCUSSION: This study is the first to have estimated the impact of atmospheric exposure to PCB153 on breast cancer risk. Our results showed a statistically significant increase in breast cancer risk, which may be limited to ER-positive breast cancer. These results warrant confirmation in further independent studies but raise the possibility that exposure to PCB153 increase breast cancer risk.

Chronic long-term exposure to cadmium air pollution and breast cancer risk in the French E3N cohort.

Cadmium, due to its estrogen-like activity, has been suspected to increase the risk of breast cancer; however, epidemiological studies have reported inconsistent findings. We conducted a case-control study (4,059 cases and 4,059 matched controls) nested within the E3N French cohort study to estimate the risk of breast cancer associated with long-term exposure to airborne cadmium pollution, and its effect according to molecular subtype of breast cancer (estrogen receptor negative/positive [ER-/ER+] and progesterone receptor negative/positive [PR-/PR+]). Atmospheric exposure to cadmium was assessed using a Geographic Information System-based metric, which included subject's residence-to-cadmium source distance, wind direction, exposure duration and stack height. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. Overall, there was no significant association between cumulative dose of airborne cadmium exposure and the risk of overall, premenopausal and postmenopausal breast cancer. However, by ER and PR status, inverse associations were observed for ER- (ORQ5 vs. Q1 = 0.63; 95% CI: 0.41-0.95, ptrend = 0.043) and for ER-/PR- breast tumors (ORQ4 vs. Q1 = 0.62; 95% CI: 0.40-0.95, ORQ5 vs. Q1 = 0.68; 95% CI: 0.42-1.07, ptrend = 0.088). Our study provides no evidence of an association between exposure to cadmium and risk of breast cancer overall but suggests that cadmium might be related to a decreased risk of ER- and ER-/PR- breast tumors. These observations and other possible effects linked to hormone receptor status warrant further investigations.

Social deprivation is associated with poor kidney transplantation outcome in children.

Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation.

Prolonged dialysis duration is associated with graft failure and mortality after kidney transplantation: results from the French transplant database.

BACKGROUND: Kidney transplantation (KT) is the treatment of choice for end-stage renal disease. Preemptive KT (PKT) should be considered when glomerular filtration rate is <15 mL/min/1.73 m2 but European reports on the results of PKT and the effect of pretransplant dialysis are scarce. METHODS: We analysed all first kidney-only transplants performed in adults in France between 2002 and 2012. A Cox multivariable model was used to investigate the association of PKT and of pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis or retransplant, whichever occurred first. RESULTS: We included 22 345 patients, with a mean ± SD age at KT of 50.5 ± 13.4 years; 61.9% were men and 3112 (14.0%) received a PKT. Median time of follow-up was 4.7 years. Graft failure occurred in 4952 patients up to 31 December 2013. After adjustment for recipients' age and sex, primary kidney disease, donor type (living or deceased donor, expanded criteria donor), HLA mismatches, cold ischaemia time, centre and year of transplantation, PKT was associated with a decreased hazard of graft failure when compared with pretransplant dialysis [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.51-0.63], whatever the duration of dialysis, even in the first 6 months. The effect of PKT on the hazard of graft failure was stronger in living kidney donors (HR 0.32; 95% CI 0.19-0.55). CONCLUSIONS: In France, PKT was associated with a lower risk of graft failure than KT performed after the initiation of dialysis, whatever the duration of dialysis.

Inverse probability weighting to control confounding in an illness-death model for interval-censored data.

Multistate models with interval-censored data, such as the illness-death model, are still not used to any considerable extent in medical research regardless of the significant literature demonstrating their advantages compared to usual survival models. Possible explanations are their uncommon availability in classical statistical software or, when they are available, by the limitations related to multivariable modelling to take confounding into consideration. In this paper, we propose a strategy based on propensity scores that allows population causal effects to be estimated: the inverse probability weighting in the illness semi-Markov model with interval-censored data. Using simulated data, we validated the performances of the proposed approach. We also illustrated the usefulness of the method by an application aiming to evaluate the relationship between the inadequate size of an aortic bioprosthesis and its degeneration or/and patient death. We have updated the R package multistate to facilitate the future use of this method.

Time-dependent effect of intensity of smoking and of occupational exposure to asbestos on the risk of lung cancer: results from the ICARE case-control study.

OBJECTIVE: To estimate the impact of intensity of both smoking and occupational exposure to asbestos on the risk of lung cancer throughout the whole exposure history. METHODS: Data on 2026 male cases and 2610 male controls came from the French ICARE (Investigation of occupational and environmental causes of respiratory cancers) population-based, case-control study. Lifetime smoking history and occupational history were collected from standardised questionnaires and face-to-face interviews. Occupational exposure to asbestos was assessed using a job exposure matrix. The effects of annual average daily intensity of smoking (reported average number of cigarettes smoked per day) and asbestos exposure (estimated average daily air concentration of asbestos fibres at work) were estimated using a flexible weighted cumulative index of exposure in logistic regression models. RESULTS: Intensity of smoking in the 10 years preceding diagnosis had a much stronger association with the risk of lung cancer than more distant intensity. By contrast, intensity of asbestos exposure that occurred more than 40 years before diagnosis had a stronger association with the risk of lung cancer than more recent intensity, even if intensity in the 10 years preceding diagnosis also had a significant effect. CONCLUSION: Our results illustrate the dynamic of the effect of intensity of both smoking and occupational exposure to asbestos on the risk of lung cancer. They confirm that the timing of exposure plays an important role, and suggest that standard analytical methods assuming equal weights of intensity over the whole exposure history may be questionable.

Risk prediction models for graft failure in kidney transplantation: a systematic review.

Risk prediction models are useful for identifying kidney recipients at high risk of graft failure, thus optimizing clinical care. Our objective was to systematically review the models that have been recently developed and validated to predict graft failure in kidney transplantation recipients. We used PubMed and Scopus to search for English, German and French language articles published in 2005-15. We selected studies that developed and validated a new risk prediction model for graft failure after kidney transplantation, or validated an existing model with or without updating the model. Data on recipient characteristics and predictors, as well as modelling and validation methods were extracted. In total, 39 articles met the inclusion criteria. Of these, 34 developed and validated a new risk prediction model and 5 validated an existing one with or without updating the model. The most frequently predicted outcome was graft failure, defined as dialysis, re-transplantation or death with functioning graft. Most studies used the Cox model. There was substantial variability in predictors used. In total, 25 studies used predictors measured at transplantation only, and 14 studies used predictors also measured after transplantation. Discrimination performance was reported in 87% of studies, while calibration was reported in 56%. Performance indicators were estimated using both internal and external validation in 13 studies, and using external validation only in 6 studies. Several prediction models for kidney graft failure in adults have been published. Our study highlights the need to better account for competing risks when applicable in such studies, and to adequately account for post-transplant measures of predictors in studies aiming at improving monitoring of kidney transplant recipients.

Identifying subgroups of renal function trajectories.

Background: Renal function in patients with chronic kidney disease (CKD) may follow different trajectory profiles. The aim of this study was to evaluate and illustrate the ability of the latent class linear mixed model (LCMM) to identify clinically relevant subgroups of renal function trajectories within a multicenter hospital-based cohort of CKD patients. Methods: We analysed data from the NephroTest cohort including 1967 patients with all-stage CKD at baseline who had glomerular filtration rate (GFR) both measured by 51 Cr-EDTA renal clearance (mGFR) and estimated by the CKD-EPI equation (eGFR); 1103 patients had at least two measurements. The LCMM was used to identify subgroups of GFR trajectories, and patients' characteristics at baseline were compared between the subgroups identified. Results: Five classes of mGFR trajectories were identified. Three had a slow linear decline of mGFR over time at different levels. In the two others, patients had a high level of mGFR at baseline with either a strong nonlinear decline over time ( n = 11) or a nonlinear improvement ( n = 94) of mGFR. Higher levels of proteinuria and blood pressure at baseline were observed in classes with either severely decreased mGFR or strong mGFR decline over time. Using eGFR provided similar findings. Conclusion: The LCMM allowed us to identify in our cohort five clinically relevant subgroups of renal function trajectories. It could be used in other CKD cohorts to better characterize their different profiles of disease progression, as well as to investigate specific risk factors associated with each profile.

Dose-time-response association between occupational asbestos exposure and pleural mesothelioma.

OBJECTIVES: Early occupational exposure to asbestos has been shown to be associated with an increased risk of pleural mesothelioma (PM), which suggests that the timing of exposure might play a role in the dose-response relationship. However, none studies has evaluated the relative impact of increasing the annual intensity of occupational exposure to asbestos at each time of the whole exposure history. Yet such evaluation would allow the comparison of the risks of PM associated with different longitudinal profiles of occupational exposure to asbestos. Our objective was to estimate the time-dependent relative impact of asbestos exposure intensity over the whole occupational history and to compare the resulting estimated risks of PM associated with different profiles of exposure, using data from a large French case-control study. METHODS: This study included 1196 male cases recruited in 1987-2006 and 2369 matched controls on birth year. Occupational exposure to asbestos was assessed using a job exposure matrix and represented in logistic regression models using a flexible weighted cumulative index of exposure. RESULTS: Due to much stronger weights of early doses of asbestos exposure, subjects who accumulated 20 fibres/mL over their entire job history with high doses during the first years and low doses thereafter were at higher risk of PM than those who accumulated most of the doses later (OR=2.37 (95% CI 2.01 to 2.87)). CONCLUSION: This study provides new insights on the dose-time-response relationship between occupational asbestos and PM and illustrates the importance of considering timing of exposure in its association with cancer risk.

Bridging the etiologic and prognostic outlooks in individualized assessment of absolute risk of an illness: application in lung cancer.

Assessment of individual risk of illness is an important activity in preventive medicine. Development of risk-assessment models has heretofore relied predominantly on studies involving follow-up of cohort-type populations, while case-control studies have generally been considered unfit for this purpose. To present a method for individualized assessment of absolute risk of an illness (as illustrated by lung cancer) based on data from a 'non-nested' case-control study. We used data from a case-control study conducted in Montreal, Canada in 1996-2001. Individuals diagnosed with lung cancer (n = 920) and age- and sex-matched lung-cancer-free subjects (n = 1288) completed questionnaires documenting life-time cigarette-smoking history and occupational, medical, and family history. Unweighted and weighted logistic models were fitted. Model overfitting was assessed using bootstrap-based cross-validation and 'shrinkage.' The discriminating ability was assessed by the c-statistic, and the risk-stratifying performance was assessed by examination of the variability in risk estimates over hypothetical risk-profiles. In the logistic models, the logarithm of incidence-density of lung cancer was expressed as a function of age, sex, cigarette-smoking history, history of respiratory conditions and exposure to occupational carcinogens, and family history of lung cancer. The models entailed a minimal degree of overfitting ('shrinkage' factor: 0.97 for both unweighted and weighted models) and moderately high discriminating ability (c-statistic: 0.82 for the unweighted model and 0.66 for the weighted model). The method's risk-stratifying performance was quite high. The presented method allows for individualized assessment of risk of lung cancer and can be used for development of risk-assessment models for other illnesses.

Analysis of risk factors associated with renal function trajectory over time: a comparison of different statistical approaches.

BACKGROUND: The most commonly used methods to investigate risk factors associated with renal function trajectory over time include linear regression on individual glomerular filtration rate (GFR) slopes, linear mixed models and generalized estimating equations (GEEs). The objective of this study was to explain the principles of these three methods and to discuss their advantages and limitations in particular when renal function trajectories are not completely observable due to dropout. METHODS: We generated data from a hypothetical cohort of 200 patients with chronic kidney disease at inclusion and seven subsequent annual measurements of GFR. The data were generated such that both baseline level and slope of GFR over time were associated with baseline albuminuria status. In a second version of the dataset, we assumed that patients systematically dropped out after a GFR measurement of <15 mL/min/1.73 m(2). Each dataset was analysed with the three methods. RESULTS: The estimated effects of baseline albuminuria status on GFR slope were similar among the three methods when no patient dropped out. When 32.7% dropped out, standard GEE provided biased estimates of the mean GFR slope in normo-, micro- and macroalbuminuric patients. Linear regression on individual slopes and linear mixed models provided slope estimates of the same magnitude, likely because most patients had at least three GFR measurements. However, the linear mixed model was the only method to provide effect estimates on both slope and baseline level of GFR unaffected by dropout. CONCLUSION: This study illustrates that the linear mixed model is the preferred method to investigate risk factors associated with renal function trajectories in studies, where patients may dropout during the study period because of initiation of renal replacement therapy.

Chances and challenges of using routine data collections for renal health care research.

BACKGROUND: Collections of electronic medical records (EMRs) can provide a rich source of information for renal health care research. However, their use in statistical analyses requires many preparatory steps, including coding of freetext entries and clear definitions of time windows for harvesting prognostic factors and outcomes. We analyse a large collection of EMRs to identify prognostic factors of adequate health care in diabetic patients at risk for chronic kidney disease, and discuss benefits and risks of such re-use of routine data. METHODS: In a representative sample of 695 068 patient records collected in 58 Austrian general practitioners' offices, we could identify 31 374 patients with diabetes mellitus. As outcomes, we investigated whether a patient received a serum creatinine measurement, and the time elapsing between two consecutive serum creatinine measurements. Prognostic factors were defined by extracting previous diagnoses, laboratory measurements, drug prescriptions and demographic characteristics from the records. RESULTS: Serum creatinine was measured annually in 44.4% of diabetic patients with previous signs of reduced kidney function and in 20.5% of the patients without such signs. Within 1 year after the first measurement, a follow-up measurement was made in 79.4 and 68.4% of the patients, respectively. Previous diagnoses, laboratory measurements, drug prescriptions and demographic characteristics explained 41% of the observed variance of kidney function monitoring. With 24% explained variance, previous referrals to laboratories were identified as the most important prognostic factor group. CONCLUSIONS: The analysis of large routine data collections poses various challenges, among which the need for coding free text into variables and various sources of biases are most demanding. However, routine data collections represent the daily practice of health care and offer many chances for renal health services and outcomes research.