Cumulative Incidence Estimates Research Articles

Understanding the impact of racism on surgical outcomes in settler nation-states USA and Canada: a protocol for a systematic review and meta-analysis

IntroductionTo improve surgical quality and safety, health systems must prioritise equitable care for surgical patients. Racialised patients experience worse postoperative outcomes when compared with non-racialised surgical patients in settler colonial...

Racial Disparities in Future Development of Lethal Prostate Cancer Based on Midlife Baseline Prostate-Specific Antigen.

Previous studies found that Midlife Baseline PSA (MB PSA) predicts the risk of developing lethal prostate cancer (PCa), although the cohorts were homogenous in terms of racial compositions. We aimed to investigate racial disparities in the predictive value of MB PSA for lethal PCa in a diverse, contemporary, North American population. Our cohort included White and Black men aged 40-59 years, who underwent MB PSA through our health system. Cumulative incidence curves depicted lethal PCa stratified by race and MB PSA above/below the median. We utilized time-dependent Receiver Operating Characteristic (ROC) curves and Area Under the ROC Curve (AUC) to compare the performance of MB PSA in predicting lethal PCa based on race. Multivariable regression (MVA) was used to examine the impact of the MB PSA in predicting lethal PCa by race. We included 112,967 men, of whom 27% were Black. The cumulative incidence estimate with MB PSA values equal to the median at 15 years of follow-up was 0.13 (0.04, 0.32) for White men and 0.55 (0.24, 1.11) for Black men. AUCs comparison showed no statistically significant differences in the predictive role of MB PSA for lethal PCa between White and Black men. At MVA, using White patients with PSA ≤ median as the reference group, the HR of lethal PCa for White men with PSA > median aged 40-44, 45-49, 50-54, and 55-59 was respectively 2.98 (1.59-5.57), 3.01 (1.89-4.81), 5.10 (3.38-7.70), and 3.38 (2.32-4.92). While for Black men was respectively 5.50 (2.94-10.27), 4.19 (2.59-6.78), 9.79 (6.37-15.04), and 7.53 (5.03-11.26) (all p < 0.001). Our findings indicate that for the same MB PSA and within the same age category, Black men have a greater risk of developing lethal PCa than White men. A separate cut-off should be created for MB PSA, if this is to be used to guide PSA screening in clinical practice.

Active surveillance follow-up for prostate cancer: from guidelines to real-world clinical practice.

To assess active surveillance (AS) adherence for prostate cancer (PCa) in a "real-world" clinical practice. We utilized our institutional database which was built by interrogating electronic medical records for all men who got diagnosed with PCa from 1995 to 2022. Our cohort included all patients aged < 76 years, with PCa Gleason Grade (GG) 1 or 2, ≤ cT2c, PSA ≤ 20 ng/ml at diagnosis, enrolled on AS, and with at least one biopsy after diagnosis. Patients were separated into two groups based on the monitoring intensity. Patients with at least 1 PSA/year and at least 1 biopsy every 4 years were categorized as adherent to guidelines. Univariable and Multivariable logistic regression analyses were used to examine the impact of covariates on non-adherence to guidelines. Competing risks cumulative incidence was used to depict prostate cancer-specific mortality (PCSM). A total of 546 men met the inclusion criteria. Overall, 63 (11%) patients were adherent to guidelines (Group 1), while 483 (89%) were not (Group 2). Median PSAs/year and median biopsies/year were 2.3 (2.0-2.7) and 0.4 (0.3-0.6) for Group 1, and 1.2 (0.7-1.8) and 0.2 (0.1-0.2) for Group 2, respectively (both p < 0.0001). At multivariable analysis, Black men had a 2.20-fold higher risk of being in Group 2 than White men (p < 0.05). Patients with cT2 (OR:0.24, CI:0.11-0.52) and those with CCI ≥2 (OR:0.40, CCI:0.19-0.82) were less likely to be in Group 2, when compared to cT1 stage and CCI = 0, respectively (both p < 0.05). At 10 years, the cumulative incidence estimate of PCSM for the entire cohort was 2.1%. We found substantial deviations from AS monitoring guidelines, particularly in biopsy frequency, which did not seem to compromise PCSM in patients with stable PSA. Notably, our findings suggest that strict adherence to guidelines, especially in patients with cT2 at diagnosis, remains crucial.

Association of race and area of deprivation index with prostate cancer incidence and lethality: results from a contemporary North American cohort.

Socioeconomic and demographic factors contribute to disparity in prostate cancer (PCa) outcomes. We examined the impact of Area of Deprivation Index (ADI) and race on PCa incidence and lethality in a North American cohort. Our cohort included men who received at least 1prostate-Specifig Antigen (pSA) test within our Health System (1995-2022). An ADI score was assigned to each patient based on their residential census block, ranked as a percentile of deprivation relative to the national level. Individuals were further categorized into quartiles, where the fourth one (ADI 75-100) represented those living in the most deprived areas. We investigated PCa incidence and lethality, using cumulative incidence estimates and competing-risk regression. An ADI × Race interaction term examined whether the relationship between ADI and outcomes varied based on race. We included 134 366 patients, 25% of whom were non-Hispanic Black (NHB). Median (IQR) follow-up was 8.8 (5-17) years. At multivariate analysis, individuals from the third quartile (ADI 50-74, 95% CI = 0.83 to 0.95) and the fourth quartile (ADI ≥75, 95% CI = 0.75 to 0.86) showed significant reduced hazard ratios for PCa incidence, when compared with the first quartile (ADI <25, all P < .001). In contrast to the overall cohort, PCa incidence increased with ADI in NHB men, who were persistently at higher hazard for both PCa incidence and lethality than non-Hispanic White (NHW), across all ADI strata (all P < .001). Living in more deprived areas was associated with lower PCa incidence and higher lethal disease rate. Conversely, PCa incidence increased with ADI for NHB, who consistently showed worse outcomes than NHW individuals, regardless of ADI.

Effects of restrictive vs liberal transfusion strategies on mortality in patients with acute myocardial infarction and anemia: The 6-month follow up primary results of the MINT trial

Abstract Background The Myocardial Ischemia and Transfusion (MINT) trial identified a statistically non-significant increase in risk of 30-day death or myocardial infarction (MI) (primary endpoint) and all-cause death and a statistically significant increase in cardiac death in patients with an acute MI and anemia assigned to a restrictive transfusion strategy compared to a liberal transfusion strategy. Purpose To determine the effect of a restrictive versus a liberal transfusion strategy on all-cause and cause-specific death 6-months post-randomization (secondary endpoint). Methods The MINT trial randomized 3,504 patients with MI and hemoglobin &amp;lt;10 g/dL to a restrictive (hemoglobin threshold of 7 or 8 g/dL) or liberal (hemoglobin threshold of &amp;lt;10 g/dL) transfusion strategy implemented during the index hospitalization. Sites contacted patients at 30-days and 6-months post-randomization and recorded patient vital status, date of death, and site-reported cause of death (categorized as cardiac, non-cardiac, or unknown). A competing risk analysis (cumulative incidence estimation and Fine-Gray models) was conducted to estimate the effect of transfusion strategy on all-cause and cause-specific death. Results Patients were enrolled from 6 countries between 2017 and 2023; average age was 72 years, and 46% were female. Vital status at 6-months was obtained for 3419 (97.6%) randomized patients (restrictive: 98.1%; liberal: 97.0%); 2,690 (76.8%) patients were alive and 729 (20.8%) had died. At 6-months, all-cause death occurred in 376 patients in the restrictive arm (21.7%) and 353 in the liberal arm (20.5%), hazard ratio [HR]: 1.07, 95% CI: 0.93–1.24. Compared to the liberal arm, a greater proportion of deaths in the restrictive arm were cardiac (41.8% vs. 29.8%). The risk of cardiac death was significantly higher in patients in the restrictive arm (9.0% vs. 6.1%, HR: 1.52; 95% CI: 1.19–1.94) whereas risk of non-cardiac death (HR: 0.87; 95% CI: 0.70–1.08) and unknown cause of death (HR: 0.88; 95% CI: 0.64–1.21) did not differ between the restrictive and the liberal arms. Conclusions In patients with acute MI and anemia, the 6-month incidence of all-cause death did not differ with a restrictive versus a liberal transfusion strategy. However, the numerically higher rate of all-cause mortality, seen with the restrictive strategy at 30-days, persisted through 6-months and was driven by cardiac causes. The long-term findings from the MINT trial suggest that a restrictive transfusion strategy may be harmful for patients with MI and anemia.

Association of race with incidence, characteristics, and mortality from incidental prostate cancer: Analysis of two North American contemporary cohorts.

Non-Hispanic Black (NHB) men are at higher risk both for incidence and mortality from prostate cancer (PCa) compared to Non-Hispanic White (NHW) men, but these findings arise from biopsy-detected PCa reports. We aimed to compare the incidence, subsequent management and cancer-specific mortality (CSM) of incidental PCa among NHB and NHW men, using two different North American cohorts. The Surveillance, Epidemiology and End-Result (SEER: 2004-2017) and our institutional Henry Ford Health (HFH: 1995-2022) databases were queried to identify men diagnosed with incidental PCa. Cumulative incidence estimates were used to calculate CSM differences between NHB and NHW men. Competing-risk multivariable regression analysis tested the impact of race on CSM, after accounting for all available covariates. A total of 418 and 6,124 incidental PCa cases were recorded in HFH and SEER database respectively. No pathological differences were observed between NHB and NHW men in both the cohorts, except for prostate-specific antigen (PSA) value at diagnosis, which was higher in NHB men. At 10-years, the CSM rates were 5.5% vs 7.2% in our cohort and 8.6% vs 10.3% in the SEER cohort for NHW and NHB men, respectively (all Gray's test p-value > 0.05). At multivariable, race was not an independent predictor of CSM in our HFH cohort (HR: 1.46, 95% CI: 0.57-3.71, p = 0.6). In the SEER cohort, NHB men were 34% less likely to die from PCa from 1 year to the next (95% CI: 0.49-0.90, p = 0.008), when compared with NHW men. In the comparison of incidental PCa findings between NHB and NHW men, both groups had similar pathological characteristic and survival outcomes. These findings are different from the 'conventional' screening-detected PCa and suggest that racial differences have minimal to no adverse effects on PCa-specific mortality after incidental diagnosis.

High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study.

The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs). A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity. The incidence and recurrence of ADEs over years of clozapine use, their effect on clozapine discontinuation and deaths, and their pharmacogenetics were studied. Median follow-up time after clozapine initiation was 12.7 years. Across 2,157 diseases and health-related events, 27 were enriched during clozapine use, falling into five disease categories: gastrointestinal hypomotility, seizures, pneumonia, other acute respiratory tract infections, and tachycardia, along with a heterogeneous group including neutropenia and type 2 diabetes, among others. Cumulative incidence estimates for ileus (severe gastrointestinal hypomotility) and pneumonia were 5.3% and 29.5%, respectively, 20 years after clozapine initiation. Both events were significantly associated with increased mortality among clozapine users (ileus: odds ratio=4.5; pneumonia: odds ratio=2.8). Decreased genotype-predicted CYP2C19 and CYP1A2 activities were associated with higher pneumonia risk. Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures.

Mental and neurodevelopmental health needs of Aboriginal children with experience of out-of-home care: a Western Australian data-linkage study

ObjectiveTo identify additional mental and neurodevelopmental health needs of Aboriginal children born in Western Australia, who are placed in out-of-home care (OOHC), relative to Aboriginal children born in Western Australia who were not placed. MethodsData-linkage of hospitalisations, health registries and child protective services data for all Aboriginal children born in WA between 2000 and 2013 was used. Children placed in out-of-home care between 2000 and 2019 were matched to children never placed and prevalence and cumulative incidence estimates of mental and neurodevelopmental health conditions were compared. ResultsChildren placed in out-of-home care had a three times greater prevalence of mental and neurodevelopmental health conditions generally. The prevalence of foetal alcohol spectrum disorder was ten times higher, and post-traumatic stress disorder was seven times higher for those placed in out-of-home care. Cumulative incidence plots highlighted for different conditions the ages at which the rate of diagnosis diverges between the two groups. ConclusionsChildren placed in out-of-home care had greater mental and neurodevelopmental health needs generally when compared to children never placed in out-of-home care . Implications for Public HealthChild protective services must ensure culturally safe, comprehensive, wrap-around services for Aboriginal children and their families are provided. Approaches should build on the strength of children, families and culture and avoid stigmatising children and their parents.

Long-term survival after unrelated donor marrow transplantation for aplastic anaemia after optimized conditioning regimen: a retrospective multicentre cohort study

Almost all acquired severe aplastic anaemia is immune mediated and characterised by hypocellular bone marrow and ≥2 affected haematopoietic lineages. The optimal preparartive regimen for unrelated donor transplantation remains to be established. We aimed to study long-term outcomes after unrelated donor transplantation for severe aplastic anaemia with de-escalation of cyclophosphamide (Cy) dose in steps of 50mg/kg (150, 100, 50, 0mg/kg) in combination with total body irradiation (TBI) 2Gy, anti-thymocyte globulin (ATG) and fludarabine. Ninety-six patients with severe aplastic anaemia aged ≤65 years with adequate organ function enrolled on a trial of human leukocyte antigen (HLA)-matched or 1 HLA-locus mismatched unrelated donor marrow transplantation conducted between 02/2006 and 12/2013 in the United States (NCT00326417). Exclusion criteria were Karnofsky performance status of less than 60, clonal cytogenetic abnormalities and inherited marrow failure syndormes. The primary outcome was day-100 engraftment (achievement of absolute neutrophil recovery to at least 0.5×109/L without subsequent decline) and day-100 survival. The trial determined the lowest effective Cydose as 50mg/kg (n=38) for day-100 engraftment and survival. Cy dose 100mg/kg (n=41) was also acceptable. Accrual to Cy doses 150mg/kg (n=15) and 0mg/kg (n=3) was terminated early for toxicities. The current study is an extended follow up of patients enrolled on the trial (NCT00326477) and includes 76 of 96 patients alive ≥1 year after transplantation. There were 20 deaths in the first year after transplantation (Cy 0mg/kg [n=2], Cy 50mg/kg [n=1], Cy 100mg/kg [n=10], Cy 150mg/kg [n=7]). Patients were followed prospectively from transplantation and data reported using standardized data collection forms until death, loss to follow up or last contact through November 2023. The incidence of graft failure was calculated using the cumulative incidence estimator and the probability of survival using the Kaplan-Meier estimator. The median follow up of the cohort is 8.02 (IQR) 5.16-10.12) years. With Cy 50mg/kg, there was one graft failure and five deaths ≥1 year after transplantation. With Cy 100mg/kg there was only one late death and no graft failure. The 8-year probabilities of survival were 85.0% (95% CI 67.3-93.5) and 75.6% (95% CI 59.4-86.1) after Cy50mg/kg and 100mg/kg, respectively, P=0.31. With Cy 0mg/kg and 150mg/kg, there were no graft failures or death ≥1 year after transplantation. Regardless of Cy dose 12 of 15 patients aged ≥50 years died. Cy 50mg/kg or 100mg/kg with TBI 2Gy, ATG and fludarabine are effective conditioning regimens for unrelated donor marrow transplants for aplastic anaemia. Identification of an optimized transplantation approach for patients aged ≥50 years is needed. US National Institutes of Health.

Hazard Ratios and Alternative Effect Measures: AnAppliedIllustration.

Although the limitations of hazard ratios (HRs) for quantifying treatment effects in right-censored data have been widely discussed, HRs are still preferentially reported over other, more interpretable effect measures. This may stem from the fact that there are few applied examples that directly contrast the HR and its interpretation with alternative effect measures. We analyzed data from two randomized clinical trials comparing panitumumab plus standard-of-care chemotherapy (SOCC) with SOCC alone as first- and second-line treatment for metastatic colorectal cancer. We report the effect of treatment with panitumumab on progression-free survival (PFS) using a Cox proportional hazards model to estimate the HR and the Kaplan-Meier estimator of cumulative incidence (risk). Further analyses included examining the cumulative incidence curves; kernel-smoothed, non-parametric hazards curves; fitting the Cox model with a continuous time variable; and estimating restricted mean survival as well as median survival. The HR was 0.82 (95% confidence interval [CI]: 0.71, 0.93), while the risk ratio (or relative risk [i.e., ratio of the cumulative incidence among the treated versus comparator]) was 0.99 (95% CI: 0.96, 1.02). These two measures suggest apparently different conclusions: either a treatment benefit or no effect. Through subsequent analyses, we demonstrated that, while the cumulative incidence of the outcome was similar by the end of follow-up regardless of treatment, the panitumumab treated group experienced longer PFS than those randomized to SOCC. Substantial nonproportional hazards were evident with panitumumab treatment reducing the hazard of progression/mortality during the first ~1.75 years but associated with an increased hazard of progress/mortality thereafter. This example underscores the difficulties in interpreting HRs, particularly in the setting of qualitative violations of proportional hazards, and the value of quantifying treatment effects via multiple effect measures.

Acute kidney injury, an underrecognized feature of VEXAS syndrome.

VEXAS syndrome is an autoinflammatory disease caused by somatic mutation of UBA1 and affects multiple organ systems. Involvement of the kidneys is not well characterized. We aimed to investigate the incidence, risk factors and histopathologic features of acute kidney injury (AKI) in VEXAS syndrome. Patients with genetically confirmed UBA1 mutation consistent with VEXAS were included. Charts were manually reviewed. Cox regression analysis was used to identify variables associated with time-to-first acute kidney injury (AKI) event. For patients with a kidney biopsy, histopathologic findings were reviewed. Eighty-one patients were included, all white men, with a mean age of 66.3±8.6 years. Median (IQR) follow up was 3.5 (2.1-5.2) years during which 20 (25%) developed AKI and 22% died. AKI relapsed in 90% of cases for a median of 6 times during the follow up period. Cumulative incidence estimates (95% CI) for AKI at 1, 3 and 5 years were 6.2% (0.80-11.3%), 16.7% (7.5-25.0%) and 27.9% (14.9-38.9%), respectively. Age and baseline C-reactive protein were significantly associated with time-to-first AKI event. Six patients underwent a kidney biopsy. Findings included, plasma cell-rich interstitial nephritis (n = 3), neutrophilic-rich interstitial inflammation (n = 1), leukocytoclastic peritubular capillaritis (n = 1), and acute tubular injury (n = 1). AKI responded well to treatment with glucocorticoids but had relapse upon tapering. AKI is an underrecognized feature of VEXAS occurring in 25% of patients in this cohort. Age at diagnosis and CRP were associated with time to first AKI event during follow up. Plasma cell-rich interstitial nephritis was the most common histopathologic finding.

Carotid Plaque Score is Associated with 10-year Major Adverse Cardiovascular Events in Low-Intermediate Risk Patients Referred to a General Cardiology Community Clinic.

Atherosclerotic carotid plaque assessments have not been integrated into routine clinical practice due to the time-consuming nature of both imaging and measurements. Plaque score, Rotterdam method, is simple, quick, and only requires 4-6 B-mode ultrasound images. The aim was to assess the benefit of plaque score in a community cardiology clinic to identify patients at risk for major adverse cardiovascular events (MACE). Patients ≥40 years presenting for risk assessment were given a carotid ultrasound. Exclusions included a history of vascular disease or MACE and being >75 years. Kaplan-Meier curves and hazard ratios were performed. The left and right common carotid artery (CCA), bulb, and internal carotid artery (ICA) were given 1 point per segment if plaque present (plaque score 0 to 6). Administrative data holdings at ICES were used for 10-year event follow-up. Of 8,472 patients, 60% were females (n = 5,121). Plaque was more prevalent in males (64% vs 53.9%; P <0.0001). The 10-year MACE cumulative incidence estimate was 6.37% with 276 events (males 6.9 % vs females 6.0%; P = 0.004). Having both maximal CCA IMT <1.00 mm and plaque score = 0, was associated with less events. A plaque score <2 was associated with a low 10-year event rate (4.1%) compared to 2-4 (8.7%) and 5-6 (20%). A plaque score ≥2 can re-stratify low-intermediate risk patients to a higher risk for events. Plaque score may be used as a quick assessment in a cardiology office to guide treatment management of patients.

Age-Based Outcomes After Surgical Aortic Valve Replacement With Bioprosthetic Versus Mechanical Valves

Recommendations for prosthesis type in older patients who underwent surgical aortic valve replacement (SAVR) are established, albeit undervalidated. The purpose of this study is to compare outcomes after bioprosthetic versus mechanical SAVR across various age groups. This was a retrospective study using an institutional SAVR database. All patients who underwent isolated SAVR were compared across valve types and age strata (<65 years, 65 to 75 years, >75 years). Patients who underwent concomitant operations, aortic root interventions, or previous aortic valve replacement were excluded. Objective survival and aortic valve reinterventions were compared. Kaplan-Meier survival estimation and multivariate regression were performed. A total of 1,847 patients underwent SAVR from 2010 to 2023. A total of 1,452 patients (78.6%) received bioprosthetic valves, whereas 395 (21.4%) received mechanical valves. Of those who received bioprosthetic valves, 349 (24.0%) were aged <65 years, 627 (43.2%) were 65 to 75 years, and 476 (32.8%%) were older than 75 years. For patients who received mechanical valves, 308 (78.0%) were aged <65 years, 84 (21.3%) were between 65 and 75 years, and 3 (0.7%) were >75 years. The median follow-up in the total cohort was 6.2 (2.6 to 8.9) years. No statistically significant differences were observed in early-term Kaplan-Meier survival estimates between SAVR valve types in all age groups. However, the cumulative incidence estimates of aortic valve reintervention were significantly higher in patients aged under 65 years who received bioprosthetic than those who received mechanical valves, with 5-year reintervention rates of 5.8% and 3.1%, respectively (p = 0.002). On competing risk analysis for valve reintervention, bioprosthetic valves were significantly associated with an increased hazard of aortic valve reintervention (hazard ratio 3.35, 95% confidence interval 1.73 to 6.49, p <0.001). In conclusion, SAVR with bioprosthetic valves (particularly, in patients aged <65 years) was comparable in survival to mechanical valve SAVR but significantly associated with increased valve reintervention rates.

Cumulative incidence estimates for solid tumors after HCT in the CIBMTR and California Cancer Registry

AbstractCompared with the general population, hematopoietic cell transplantation (HCT) survivors are at elevated risk for developing solid subsequent neoplasms (SNs). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a key resource for quantifying solid SN incidence following HCT, but the completeness of SN ascertainment is uncertain. Within a cohort of 18 450 CIBMTR patients linked to the California Cancer Registry (CCR), we evaluated the completeness of solid SN data reported to the CIBMTR from 1991 to 2018 to understand the implications of using CIBMTR data alone or combined with CCR data to quantify the burden of solid SNs after HCT. We estimated the cumulative incidence of developing a solid SN, accounting for the competing risk of death. Within the cohort, solid SNs were reported among 724 patients; 15.6% of these patients had an SN reported by CIBMTR only, 36.9% by CCR only, and 47.5% by both. The corresponding cumulative incidence of developing a solid SN at 10 years following a first HCT was 4.0% (95% confidence interval [CI], 3.5-4.4) according to CIBMTR data only, 5.3% (95% CI, 4.9-5.9) according to CCR data only, and 6.3% (95% CI, 5.7-6.8) according to both sources combined. The patterns were similar for allogeneic and autologous HCT recipients. Linking detailed HCT information from CIBMTR with comprehensive SN data from cancer registries provides an opportunity to optimize SN ascertainment for informing follow-up care practices and evaluating risk factors in the growing population of HCT survivors.

A unified framework for estimating country-specific cumulative incidence for 18 diseases stratified by polygenic risk

Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS associations from seven studies in four countries (N = 1,197,129) with disease incidences from the Global Burden of Disease. PGS has a significant sex-specific effect for asthma, hip osteoarthritis, gout, coronary heart disease and type 2 diabetes (T2D), with all but T2D exhibiting a larger effect in men. PGS has a larger effect in younger individuals for 13 diseases, with effects decreasing linearly with age. We show for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. Our framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting for age- and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common diseases.

Incidence of acute kidney injury in patients with relapsed and refractory multiple myeloma treated with teclistamab vs chimeric antigen receptor T-cell therapy.

7542 Background: Teclistamab, a novel bispecific monoclonal antibody targeting CD3 and BCMA, exhibits promising effects for patients with relapsed and refractory multiple myeloma (MM). However, rates of acute kidney injury (AKI) associated with this therapy remains inadequately characterized. Methods: This was a retrospective observational cohort study of patients with relapsed refractory MM who received teclistamab or Chimeric Antigen Receptor T-cell Therapy (CAR-T) therapy at Mayo Clinic between 12/1/2022-5/15/2023 and who were not in kidney failure at the time of treatment. The primary endpoint was incidence of AKI during follow-up; secondary endpoints included treatment and recovery from AKI. AKI was defined based on Kidney Disease Improving Global Outcomes criteria as an increase of serum creatinine levels &gt; 1.5 times their baseline value after starting therapy. Cumulative incidences and Cox proportional hazard regression models were used to evaluate time to event data. Results: A total of 64 patients met inclusion criteria for the study (30 received CAR-T and 34 received teclistamab therapy). There were 14 AKI events occurring during follow-up (10 teclistamab [n = 6 stage 1, n = 3 stage 2 and n = 1 stage 3] and 4 CAR-T [n = 3 stage 1 and n = 1 stage 2]). Cumulative incidence estimates of AKI at 120 days after treatment were 32% (95% CI: 14%-47%) for teclistamab patients and 10% (95% CI: 0%-21%) for CAR-T patients. While patients receiving teclistamab were found to be at increased risk of an incident AKI event compared to patients receiving CAR-T therapy, results were not statistically significant (HR (95% CI): 3.38 (0.93-12.31), p = 0.065). Median time to development of AKI was 30 days (IQR 16, 73) in teclistamab and 59 days (IQR 9, 146) in CAR-T patients. Among the 10 patients in the teclistamab group with an AKI event, 4 (40%) had complete renal recovery and 4 (40%) had partial recovery, while among the 4 patients with CAR-T with an AKI event, 2 (50%) experienced complete renal recovery and 2 (50%) experienced partial recovery. Conclusions: Our study showed that almost one third of patients receiving teclistamab therapy for relapsed and refractory multiple myeloma experienced an incident AKI event during follow-up. This finding underscores the importance of monitoring for kidney function in these patients.

Cumulative incidence of cardiac surgery associated with exposure to benfluorex: A retrospective analysis based on compensation claims data.

Data on retrospective compensation claims for injuries caused by pharmaceutical drugs are prone to selection and reporting biases. Nevertheless, this case study of the antidiabetic drug benfluorex shows that such data can be used to estimate the cumulative incidence of drug-related injury, and to provide insights into its epidemiology. To this end, we develop a modelling framework for under-reporting of retrospective claims for compensation arising from drug damage. The model involves a longitudinal component related to attrition of cases over time, and a cross-sectional component related to incomplete reporting. We apply this model to cardiac valve surgery necessitated by exposure to benfluorex. Benfluorex was marketed in France between 1976 and 2009, when it was withdrawn because it caused valvular heart disease. A scandal erupted in 2010 over the scale of the damage caused by the drug. Since then, no further estimates of cumulative incidence have been published, though thousands of claims for compensation have been processed. The analysis combines compensation claims data and sociological survey data on benfluorex users, together with data on benfluorex sales and duration of treatment. We find a threshold of toxicity at about 6 months' exposure, and that at least 1690 individuals (95% CI 1290 to 2320) needed heart surgery to replace or repair valves damaged by exposure to benfluorex in France: a cumulative incidence of 3.68 per 10,000 (95% CI 2.68 to 5.34) benfluorex users or 3.22 per 10,000 (95% CI 2.48 to 4.39) person-years at risk above the exposure threshold. While these findings are tentative, they are consistent with those obtained previously using very different methods.

The Presence of Extensive Lymphovascular Invasion is Associated With Higher Risks of Local-Regional Recurrence Compared With Usual Lymphovascular Invasion in Curatively Treated Breast Cancer Patients

Purpose/objectives: Several datasets have demonstrated a correlation between lymph-vascular invasion (LVI) and local-regional recurrence (LRR). Whether the observation of "extensive LVI" is a further and incremental determinant of LRR risk is unknown. We describe clinical outcomes in women with invasive breast cancer stratified by: 1) absence of LVI (neg), 2) LVI focal or suspicious (FS-LVI), 3) usual (non-extensive) LVI (LVI) and 4) extensive LVI (E-LVI).Materials/Methods: Between 12/2009 and 8/2021, 8837 patients with early-stage breast cancer were treated with curative intent and were evaluable. Clinical-pathological details were abstracted by retrospective review. The description of LVI was abstracted from pathology reports. Recurrence and survival outcomes were compared based on the extent of LVI. A matched propensity score analysis compared outcomes between patients with LVI vs. E-LVI.Results: Of the 8837 patients studied, 5584 were neg, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. Patient with E-LVI had an adverse risk profile compared to the other groups.The 5- and 10-year local regional recurrence (LRR) cumulative incidence estimates in patients with E-LVI were 9.6% (95% CI: 7.1-13) and 13% (95% CI: 10-17), which were significantly higher than observed in the usual LVI group (6.8% [5.7-7.9] and 10% [8.8-12], respectively). A statistically significant difference in LRR was demonstrated on univariable (HR 1.4, 95% CI [1.03-1.89], p-value 0.029) and multivariable regression analysis (HR 1.62, 95% CI [1.15-2.27], p-value 0.005) when compared to non-extensive LVI.In an alternative approach, we performed a 2:1 propensity-matched analysis comparing LVI to E-LVI patients. The hazard ratio for LRR (HR 1.47 (CI 1.02-2.14, p=0.041) was suggestive of a higher risk with E-LVI.Conclusions: Our work suggests that patients with E-LVI are at a higher risk for LRR than those with usual LVI. For patients who are borderline candidates for regional nodal irradiation or PMRT, the finding of E-LVI might be decisive in favor of intensified treatment.

Racial disparities in stage at bladder cancer diagnosis in the US Veterans Affairs healthcare system.

To describe patient characteristics and pathological stage at bladder cancer (BCa) diagnosis in a diverse population within a national, equal-access healthcare system. This retrospective cohort study identified 15 966 men diagnosed with BCa in the Veterans Affairs (VA) healthcare system from 2000 to 2020. The primary outcome was pathological stage at diagnosis, determined by index transurethral resection of bladder tumour. Logistic regression was used to assess the relationship between race and stage. Competing risk models tested the association between race and BCa-specific mortality with cumulative incidence estimates. Of 15 966 BCa patients, 12 868 (81%), 1726 (11%), 493 (3%) and 879 (6%) were White, Black, Hispanic and Other race, respectively. Black patients had significantly higher muscle-invasive bladder cancer (MIBC) rates than White patients (35% vs 32%; P = 0.009). In multivariable analysis, the odds of presenting with MIBC did not differ significantly between Black and White patients (odds ratio [OR] 1.10, 95% confidence interval [CI] 0.98-1.22) or between Hispanic patients (OR 0.82, 95% CI 0.67-1.01) and White patients. Compared to White patients, Black patients had a similar risk of BCa-specific mortality (hazard ratio [HR] 0.89, 95% CI 0.75-1.06), whereas Hispanic patients had a lower risk (HR 0.56, 95% CI 0.38-0.82). Black patients presented with the highest rates of de novo MIBC. However, in a large, equal-access healthcare system, this did not result in a difference in BCa-specific mortality. In contrast, Hispanic patients had lower risks of MIBC and BCa-specific mortality.

Estimating SARS-CoV-2 infection probabilities with serological data and a Bayesian mixture model

The individual results of SARS-CoV-2 serological tests measured after the first pandemic wave of 2020 cannot be directly interpreted as a probability of having been infected. Plus, these results are usually returned as a binary or ternary variable, relying on predefined cut-offs. We propose a Bayesian mixture model to estimate individual infection probabilities, based on 81,797 continuous anti-spike IgG tests from Euroimmun collected in France after the first wave. This approach used serological results as a continuous variable, and was therefore not based on diagnostic cut-offs. Cumulative incidence, which is necessary to compute infection probabilities, was estimated according to age and administrative region. In France, we found that a “negative” or a “positive” test, as classified by the manufacturer, could correspond to a probability of infection as high as 61.8% or as low as 67.7%, respectively. “Indeterminate” tests encompassed probabilities of infection ranging from 10.8 to 96.6%. Our model estimated tailored individual probabilities of SARS-CoV-2 infection based on age, region, and serological result. It can be applied in other contexts, if estimates of cumulative incidence are available.