Inverse Probability Of Censoring Weights Research Articles

Attention-deficit hyperactivity disorder symptoms and brain morphology: Addressing potential selection bias with inverse probability weighting.

The goal of this study was to examine what happens to established associations between attention deficit hyperactivity disorder (ADHD) symptoms and cortical surface and thickness regions once we apply inverse probability of censoring weighting (IPCW) to address potential selection bias. Moreover, we illustrate how different factors that predict participation contribute to potential selection bias. Participants were 9- to 11-year-old children from the Generation R study (N = 2707). Cortical area and thickness were measured with magnetic resonance imaging (MRI) and ADHD symptoms with the Child Behavior Checklist. We examined how associations between ADHD symptoms and brain morphology change when we weight our sample back to either follow-up (ages 9-11), baseline (cohort at birth), or eligible (population of Rotterdam at time of recruitment). Weights were derived using IPCW or raking and missing predictors of participation used to estimate weights were imputed. Weighting analyses to baseline and eligible increased beta coefficients for the middle temporal gyrus surface area, as well as fusiform gyrus cortical thickness. Alternatively, the beta coefficient for the rostral anterior cingulate decreased. Removing one group of variables used for estimating weights resulted in the weighted regression coefficient moving closer to the unweighted regression coefficient. In addition, we found considerably different beta coefficients for most surface area regions and all thickness measures when we did not impute missing covariate data. Our findings highlight the importance of using inverse probability weighting (IPW) in the neuroimaging field, especially in the context of mental health-related research. We found that including all variables related to exposure-outcome in the IPW model and combining IPW with multiple imputations can help reduce bias. We encourage future psychiatric neuroimaging studies to define their target population, collect information on eligible but not included participants and use inverse probability of censoring weighting (IPCW) to reduce selection bias.

Target Trial Emulation: Does surgical versus non-surgical management of cranial cruciate ligament rupture in dogs cause different outcomes?

Target trial emulation applies design principles from randomised controlled trials to the analysis of observational data for causal inference and is increasingly used within human epidemiology. Using anonymised veterinary clinical data from the VetCompass Programme, this study applied the target trial emulation framework to determine whether surgical (compared to non-surgical) management for cranial cruciate ligament (CCL) rupture in dogs causes improved short- and long-term lameness and analgesia outcomes.The emulated target trial included dogs diagnosed with CCL rupture between January 1, 2019 and December 31, 2019 within the VetCompass database. Inclusion in the emulated trial required dogs aged ≥ 1.5 and < 12 years, first diagnosed with unilateral CCL rupture during 2019 and with no prior history of contralateral ligament rupture or stifle surgery. Dogs were retrospectively observed to have surgical or non-surgical management. Informed from a directed acyclic graph derived from expert opinion, data on the following variables were collected: age, breed, bodyweight, neuter status, insurance status, non-orthopaedic comorbidities, orthopaedic comorbidities and veterinary group. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding, with weights calculated based on a binary logistic regression exposure model. Censored dogs were accounted for in the IPTW analysis using inverse probability of censoring weighting (IPCW). The IPCWs were combined with IPTWs and used to weight each dog’s contribution to binary logistic regression outcome models. Standardized mean differences (SMD) examined the balance of covariate distribution between treatment groups.The emulated trial included 615 surgical CCL rupture cases and 200 non-surgical cases. The risk difference for short-term lameness in surgically managed cases (compared with non-surgically managed cases) was −25.7% (95% confidence interval (CI) −36.7% to −15.9%) and the risk difference for long-term lameness −31.7% (95% CI −37.9% to −18.1%).The study demonstrated the application of the target trial framework to veterinary observational data. The findings show that surgical management causes a reduction in short- and long-term lameness compared with non-surgical management in dogs.

Adjusting for subsequent therapies in the TOURMALINE-MM1 study shows clinically meaningful improvement in overall survival with addition of ixazomib to lenalidomide and dexamethasone.

TOURMALINE-MM1, the only blinded randomized study in patients with relapsed and/or refractory multiple myeloma (RRMM; ≥1 prior therapy) in the last 10 years, investigated ixazomib+lenalidomide+dexamethasone (IRd) versus lenalidomide+dexamethasone (Rd). Final overall survival (OS) data were based on a median follow-up of 85 months. In RRMM trials where patients have had 1-3 relapses after initial treatment, a high proportion receive subsequent therapy. Application of salvage therapies in blinded trials and newer modes of therapy can increasingly complicate the interpretation of OS. This analysis explores the impact of subsequent therapies on OS outcomes in TOURMALINE-MM1. The inverse probability of censoring weights (IPCW) method, marginal structural model (MSM), and rank preserving structural failure time model (RPSFTM) were utilized to adjust for confounding on OS, introduced by subsequent therapies. Analyses were conducted for the intentto-treat (ITT) population and ≥2 prior lines subgroup. Unadjusted hazard ratio (HR) for IRd versus Rd was 0.94 (95% confidence interval [CI]: 0.78-1.13) in the ITT population. After adjusting for the impact of subsequent therapies by the RPSFTM method, estimated HR for IRd versus Rd in the ITT population was 0.89 (95% CI: 0.74-1.07). Adjusting with IPCW and MSM methods also showed an improvement in HR, favoring IRd. IRd may be particularly beneficial in patients with ≥2 prior lines of therapy (IPCW and MSM HR=0.52, 95% CI: 0.30-0.88; RPSFTM HR=0.68, 95% CI: 0.51-0.91). These analyses highlight the growing challenge of demonstrating OS benefit in multiple myeloma patients and the importance of assessing confounding introduced by subsequent therapies when interpreting OS.

Estimating median overall survival of apalutamide compared to placebo in metastatic hormone-sensitive prostate cancer (mHSPC) populations: Statistical extrapolations of the TITAN study.

223 Background: Apalutamide plus ADT (APA) demonstrated significantly improved overall survival (OS) compared to placebo plus ADT (PBO) for patients with mHSPC in the TITAN study (HR, 0.65; 95% CI, 0.53 to 0.79; P &lt; .0001). At the time of final analysis, the median OS was not reached in the APA arm or subgroups after a median follow up of 44 months. This work aimed to estimate OS medians for APA and PBO arms beyond the TITAN follow-up by fitting validated survival models. Methods: OS was predicted for the overall population treated with APA or PBO, with or without Inverse probability of censoring weighting (IPCW) crossover adjustment, and for the low and high-volume (LVD, HVD), HVD synchronous and HVD metachronous subgroups. General population mortality adjusted TITAN patient-level data was fitted to six parametric models (Weibull, exponential, log-normal, log-logistic, generalized gamma, and Gompertz) using the individual fits approach. Best fit was determined by statistical and visual fits, along with the Akaike Information Criterion (AIC)/Bayesian Information Criterion (BIC) ranking, according to the recommendations of the National Institute for Health and Care Excellence Decision Support Unit 14. Results: Best fit extrapolation estimated median OS of 71.8 months for the overall mHSPC population treated with APA (Table), leading to an estimated median improvement of up to 32 months versus PBO. Median OS values predicted by the other five models ranged from 62.4 to 78.1 months. Across subgroups, best fit models estimated median OS of 113.7 months for APA in LVD and a consistent median OS of 52 months for HVD subgroups. Conclusions: While results of this extrapolation study should not be equated to those of a clinical trial, this analysis meets an evidence gap by predicting median OS in the APA arm of the TITAN study for the overall mHSPC population as well as for various subgroups of this heterogeneous population, strengthening the evidence supporting early treatment with APA across the broad mHSPC population. [Table: see text]

A cautionary tale: an evaluation of the performance of treatment switching adjustment methods in a real world case study

BackgroundTreatment switching in randomised controlled trials (RCTs) is a problem for health technology assessment when substantial proportions of patients switch onto effective treatments that would not be available in standard clinical practice. Often statistical methods are used to adjust for switching: these can be applied in different ways, and performance has been assessed in simulation studies, but not in real-world case studies. We assessed the performance of adjustment methods described in National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 16, applying them to an RCT comparing panitumumab to best supportive care (BSC) in colorectal cancer, in which 76% of patients randomised to BSC switched onto panitumumab. The RCT resulted in intention-to-treat hazard ratios (HR) for overall survival (OS) of 1.00 (95% confidence interval [CI] 0.82–1.22) for all patients, and 0.99 (95% CI 0.75–1.29) for patients with wild-type KRAS (Kirsten rat sarcoma virus).MethodsWe tested several applications of inverse probability of censoring weights (IPCW), rank preserving structural failure time models (RPSFTM) and simple and complex two-stage estimation (TSE) to estimate treatment effects that would have been observed if BSC patients had not switched onto panitumumab. To assess the performance of these analyses we ascertained the true effectiveness of panitumumab based on: (i) subsequent RCTs of panitumumab that disallowed treatment switching; (ii) studies of cetuximab that disallowed treatment switching, (iii) analyses demonstrating that only patients with wild-type KRAS benefit from panitumumab. These sources suggest the true OS HR for panitumumab is 0.76–0.77 (95% CI 0.60–0.98) for all patients, and 0.55–0.73 (95% CI 0.41–0.93) for patients with wild-type KRAS.ResultsSome applications of IPCW and TSE provided treatment effect estimates that closely matched the point-estimates and CIs of the expected truths. However, other applications produced estimates towards the boundaries of the expected truths, with some TSE applications producing estimates that lay outside the expected true confidence intervals. The RPSFTM performed relatively poorly, with all applications providing treatment effect estimates close to 1, often with extremely wide confidence intervals.ConclusionsAdjustment analyses may provide unreliable results. How each method is applied must be scrutinised to assess reliability.

Comparison of baseline covariate adjustment methods for restricted mean survival time

The restricted mean survival time provides a straightforward clinical measure that dispenses with the need for proportional hazards assumptions. We focus on two strategies to directly model the survival time and adjust covariates. Firstly, pseudo-survival time is calculated for each subject using a leave-one-out approach, followed by a model analysis that adjusts for covariates using all pseudo-values. This method is used to reflect information of censored subjects in the model analysis. The second approach adjusts for covariates for those subjects with observed time-to-event while incorporating censored subjects using inverse probability of censoring weighting (IPCW). This paper evaluates these methods' power to detect group differences through computer simulations. We find the interpretation of pseudo-values challenging with the pseudo-survival time method and confirm that pseudo-survival times deviate from actual data in a primary biliary cholangitis clinical trial, mainly due to extensive censoring. Simulations reveal that the IPCW method is more robust, unaffected by the balance of censors, whereas pseudo-survival time is influenced by this balance. The IPCW method retains a nominal significance level for the type-1 error rate, even amidst group differences concerning censor incidence rates and covariates. Our study concludes that IPCW and pseudo-survival time methods differ significantly in handling censored data, impacting parameter estimations. Our findings suggest that the IPCW method provides more robust results than pseudo-survival time and is recommended, even when censor probabilities vary between treatment groups. However, pseudo-survival time remains a suitable choice when censoring probabilities are balanced.

Comparative Effectiveness of Ibrutinib Flexible Dosing Treatment Strategies on Time to Next Treatment in a Largely Community-Based Claims Database: A Target Trial Emulation Study

Introduction: Outside of a clinical trial setting, ibrutinib is the most well-characterized of the covalent Bruton's tyrosine kinase inhibitors used in the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in the first-line (1L) setting. However, the impact of ibrutinib dose adjustment on clinical outcomes remains to be defined. In this real-world effectiveness study, we compared time to next treatment (TTNT) as a proxy for disease progression for dose adjustment and standard dose treatment strategies in patients with CLL/SLL receiving 1L single-agent IBR. Methods: This study utilized the Komodo Health payer-complete dataset, derived from U.S. health insurance claims from &amp;gt;150 private insurers covering &amp;gt;160 million individuals from 2015-2023; 53% of these patients are from community centers. Adult patients with CLL/SLL were included if they initiated 1L single-agent IBR 420 mg/day between March 2016 - April 2023 (IBR initiation date = index date; 1L single-agent IBR was defined as no other CLL/SLL treatment in the 12-month baseline period or within 28 days after index). A target trial emulation (TTE) approach was utilized to compare TTNT, defined as the time between the index date to the initiation of a next line of therapy (LOT), for two treatment strategies: 1) Dose adjustment strategy, defined as a lead-in IBR treatment at 420mg/day for 3-12 months, followed by dose adjustment to &amp;lt;420mg/day until next LOT or IBR discontinuation; 2) Standard dose strategy, defined as a continuous IBR treatment at 420mg/day without any dose adjustment for &amp;gt;12 months until next LOT or IBR discontinuation. The TTE approach minimizes immortal time bias in a naïve observational analysis as patients in the dose adjustment cohort cannot initiate next LOT before dose adjustment occurs [Hernan et al. Am J Epidemiol. 2016]. To explicitly emulate a target trial, two clones were created for each patient, with one clone contributing person-time and event to each treatment strategy of interest, respectively. A clone was artificially censored when the actual treatment path deviated from the assigned treatment strategy. Selection bias due to artificial censoring was corrected using time-varying inverse probability of censoring weights (IPCW), accounting for post-index time-varying clinical factors related to IBR dose adjustment or IBR discontinuation. TTNT hazard ratio (HR; robust 95% confidence interval [CI]) was estimated using an IPCW-weighted pooled logistic regression model. Alternative lead-in periods with IBR standard dosing (3-6 and 3-9 months) were also evaluated. A subgroup analysis was conducted among patients with high cardiovascular (CV) risk, defined as having a preexisting CV comorbidity or a high CHA 2DS 2-Vasc risk score. Results: 3,342 adults initiated 1L single-agent IBR at 420 mg/day. Mean (standard deviation [SD]) age was 67.5 (10.6) years, 62% were male, and mean (SD) Quan-Charlson Comorbidity Index score was 3.0 (1.5). The median (interquartile range) follow-up duration was 19.6 (7.5, 35.0) months. During the study period, 463 patients (14%) initiated a subsequent LOT. The high CV risk subgroup consisted of 2,640 (79%) patients. In the overall study population, 608 (18%) patients experienced a dose adjustment after the index date. Of those, the dose adjustment occurred ≤3 months, ≤6 months, and ≤12 months post-index in 159 (26%), 300 (49%), and 440 (72%) patients, respectively, with dose used at the first reduction of 70 mg, 140 mg, or 280 mg in 4 (1%), 85 (14%), and 519 (85%) patients, respectively. The dose adjustment strategy (420 mg/day for 3-12 months followed by a reduced dose) was not associated with increased risk of initiating next LOT (adjusted HR [95% CI] 0.95 [0.80, 1.14]) compared to the continuous standard dose strategy; results for the alternative lead-in periods and the high CV risk subgroup were consistent with the primary scenario. Conclusions: In this real-world comparative effectiveness study with the majority of patients from community centers, dose adjustment of 1L single-agent IBR treatment for CLL/SLL is not associated with an increased risk of initiating next LOT when compared to continuous standard dose treatment. These findings suggest that a flexible dosing approach with IBR may be an effective option to maintain an optimal balance of clinical therapeutic efficacy and safety for patients with CLL/SLL in the 1L setting.

Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality

ObjectiveA post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated...

Abstract 18584: Predictive Accuracy Of The Pooled Cohort Equations For Estimating Atherosclerotic Cardiovascular Disease Risk Among Women Exposed To Potentially Cardiotoxic Breast Cancer Therapies

Introduction: Risk estimation is a critical component in clinical decision making for preventive cardiovascular care. Suboptimal identification and management of cardiovascular disease (CVD) risk, may contribute to excess CVD morbidity and mortality among breast cancer (BC) patients and survivors. This study aimed to assess the performance of the Pooled Cohort Equations (PCEs) in predicting atherosclerotic cardiovascular disease (ASCVD) events among a real-world population of adult women treated for BC. Methods: Using electronic medical record data collected between Jan. 1, 2011 and Jan. 31, 2023, this external validation study retrospectively identified a cohort of BC women, age 40-79, without history of ASCVD in the one year prior to initiation of a potentially cardiotoxic BC therapy. For all cohort members with cholesterol and blood pressure measurements recorded within one year prior to the index cancer therapy exposure (n=1,239), a 5-year ASCVD risk estimate was calculated. Predictive accuracy of the risk estimate was assessed using a Poisson model-based framework for calibration, including evaluation of calibration-in-the-large, the calibration slope, and calibration plots. To account for potential biases related to informative censoring, calibration was assessed among an inverse probability of censoring weighted (IPCW) pseudopopulation with stabilized and unstabilized weights, and a complete case cohort (n=306). Results: Among the IPCW pseudopopulation, calibration-in-the-large, expressed as a standardized incidence ratio, was 1.85 (95% CI: 1.73, 1.98), indicating that, on average, women in this subpopulation experience a significantly higher number of ASCVD events than expected from baseline PCE risk estimates. The calibration slope, estimated at 0.55 (95% CI: 0.45, 0.66), and evaluation of calibration plots, further indicate particularly poor performance of the PCEs at low and high levels of estimated risk. Findings were consistent across the assessed populations. Conclusions: When calculated prior to initiation of a potentially cardiotoxic BC therapy, the PCEs significantly underestimate 5-year ASCVD risk for BC women, indicating this commonly used ASCVD risk estimate is poorly calibrated for this subpopulation.

The net benefit for time-to-event outcome in oncology clinical trials with treatment switching.

The net benefit is an effect measure for any type of endpoint, including the time-to-event outcome, and can provide intuitive and clinically meaningful interpretation. It is defined as the probability of a randomly selected subject from the experimental arm surviving by at least a clinically relevant time longer than a randomly selected subject from the control arm. In oncology clinical trials, an intercurrent event such as treatment switching is common, which potentially causes informative censoring; nevertheless, conventional methods for the net benefit are not able to deal with it. In this study, we proposed a new estimator using the inverse probability of censoring weighting (IPCW) method and illustrated an oncology clinical trial with treatment switching (the SHIVA study) to apply the proposed method under the estimand framework. The net benefit can be estimated using the survival functions of each treatment group. The proposed estimator was based on the survival functions estimated by the inverse probability of the censoring weighting method that can handle covariate-dependent censoring. The simulation study was undertaken to evaluate the operating characteristics of the proposed estimator under several scenarios; we varied the shapes of the survival curves, treatment effect, covariates effect on censoring, proportion of the censoring, threshold of the net benefit, and sample size. We also applied conventional methods (the scoring rules by Péron or Gehan) and the proposed method to the SHIVA study. Our simulation study showed that the proposed estimator provided less biased results under the covariate-dependent censoring than existing estimators. When applying the proposed method to the SHIVA study, we were able to estimate the net benefit by incorporating the information of the covariates with different estimand strategies to address the intercurrent event of the treatment switching. However, the estimates of the proposed method and those of the aforementioned conventional methods were similar under the hypothetical strategy. We proposed a new estimator of the net benefit that can include covariates to account for the possibly informative censoring. We also provided an illustrative analysis of the proposed method for the oncology clinical trial with treatment switching using the estimand framework. Our proposed new estimator is suitable for handling the intercurrent events that can potentially cause covariate-dependent censoring.

Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma.

LBA107 Background: In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) was superior to standard of care (SOC; hazard ratio [HR], 0.398; P&lt;.0001) in the primary analysis of event-free survival as second-line therapy in patients with early relapsed or refractory large B-cell lymphoma (R/R LBCL; Locke et al. NEJM. 2022). In a preplanned interim analysis, median overall survival (OS) was not reached in the axi-cel arm and was 25.7 mo in the SOC arm (HR, 0.71; 95% CI, 0.52-0.97; Locke et al. TCT 2022. Abstract 1). We now report the primary OS analysis of ZUMA-7. Methods: Study procedures and eligibility were previously reported. The intention-to-treat (ITT) primary OS analysis occurred 5 years after the first patient was randomized (01/25/2018) per protocol. A log-rank test stratified by randomization stratification factors compared OS between the 2 arms. In addition to the ITT analysis and to account for subsequent treatment with cellular immunotherapy off protocol in the SOC arm, prespecified sensitivity analyses of OS were conducted using the Rank-Preserving Structural Failure Time (RPSFT) and Inverse Probability of Censoring Weights (IPCW) models. Other endpoints included progression-free survival (PFS) per investigator assessment, OS in key subgroups, and safety. Results: In total, 359 patients were randomly assigned, 180 to axi-cel and 179 to SOC. As of 01/25/2023, at a median follow-up of 47.2 mo, axi-cel demonstrated a statistically significant improvement in OS over SOC (HR [95% CI], 0.726 [0.540-0.977]; stratified log-rank 1-sided P=0.0168 [efficacy boundary, 0.0249]). Median OS was longer with axi-cel vs SOC (not reached vs 31.1 mo, respectively); 48-mo OS estimates were higher with axi-cel (54.6% vs 46.0%, respectively). OS benefit with axi-cel vs SOC was consistent in prespecified key subgroups, including age ≥65 years, primary refractory, early relapse, high-grade B-cell lymphoma, and high second-line age-adjusted IPI. In the SOC arm, 102 (57%) patients received subsequent cellular immunotherapy off protocol. Prespecified OS sensitivity analyses, conducted to address the confounding effects of treatment-switching in the SOC arm, showed an even greater OS benefit with axi-cel vs SOC, with stratified HR (95% CI) of 0.608 (0.449-0.824) by RPSFT and 0.633 (0.409-0.981) by IPCW. PFS by investigator confirmed benefit of axi-cel over SOC (HR [95% CI], 0.506 [0.383-0.669]), with 48-mo PFS estimates of 41.8% vs 24.4%, respectively. No new cytokine release syndrome or neurologic events and no new treatment-related deaths occurred since the primary EFS analysis. The safety profile of axi-cel remained consistent with prior studies. Conclusions: Axi-cel as second-line therapy demonstrated a significant improvement in overall survival over historical standard of care in patients with early relapsed/refractory LBCL. Clinical trial information: NCT03391466 .

Neurodevelopmental outcomes in children after prenatal marijuana exposure.

The effect of prenatal marijuana exposure (PME) on child neurodevelopment remains poorly understood. Prior studies have demonstrated inconsistent results. This study evaluated the association between PME and neuropsychological test scores in late childhood and early adulthood, accounting for a wide range of parental characteristics. This study evaluated participants from the Raine Study, a cohort of 2868 children born between 1989 and 1992. Children whose mothers provided information on marijuana use during pregnancy were included. The primary outcome was the Clinical Evaluation of Language Fundamentals (CELF) at age 10. Secondary outcomes included the Peabody Picture Vocabulary Test (PPVT), Child Behaviour Checklist (CBCL), McCarron Assessment of Neuromuscular Development (MAND), Coloured Progressive Matrices (CPM), Symbol Digit Modality Test (SDMT) and Autism Spectrum Quotient (AQ) scores. Exposed and unexposed children were matched by propensity score using optimal full matching. Missing covariate data were imputed using multiple imputation. Inverse probability of censoring weighting (IPCW) was used to adjust for missing outcome data. Linear regression within matched sets, adjusted by IPCW, evaluated score differences between exposed and unexposed children. As a secondary analysis, modified Poisson regression, adjusted by match weights and IPCW, evaluated the risk of clinical deficit in each outcome following PME. Of the 2804 children in this cohort, 285 (10.2%) had PME. After optimal full matching and IPCW, exposed children scored similarly on CELF Total (-0.33 points, 95% confidence interval [CI] -4.71, 4.05), Receptive (+0.65 points, 95% CI -4.08, 5.38) or Expressive (-0.53 points, 95% CI -5.07, 4.02). PME was not associated with secondary outcomes or risks of clinical deficit in any neuropsychological assessments. After adjusting for sociodemographic and clinical covariates, PME was not associated with worse neuropsychological test scores at age 10 or autistic traits at 19-20.

Real-world overall survival in second-line maintenance niraparib monotherapy vs active surveillance in BRCA wild-type patients with recurrent ovarian cancer.

5592 Background: The Phase 3NOVA trial assessed niraparib versus placebo as a maintenance treatment (tx) for patients (pts) with recurrent ovarian cancer (OC) who were platinum-sensitive after ≥2 regimens; progression-free survival was the primary endpoint and overall survival (OS) was a secondary endpoint (NCT01847274). The aim of this real-world study was to compare OS in a breast cancer gene wild-type ( BRCAwt) population of pts with recurrent OC and who received second-line maintenance (2Lm) niraparib monotherapy or were under active surveillance (AS). Methods: This study used the US nationwide Flatiron Health de-identified electronic health record (EHR)-derived database. Pts diagnosed with epithelial OC between 1Jan2011–31May2021 who completed 2L therapy between 1Jan2017–2Mar2022 were eligible for inclusion. Pts were BRCAwt, had an ECOG PS score 0–1, epithelial histology, and platinum-sensitive disease with ≥6 months between end of first-line tx and start of 2L tx. Pts were assigned to 2Lm niraparib or AS cohorts based on their management following 2L non-maintenance therapy (≤120 days). Follow-up was measured from the index date (end of 2L non-maintenance therapy) until end of study (31May2022), last activity, or death, whichever came first. A target trial emulation cloned inverse probability of censoring weighting (IPCW) methodology was selected a priori to minimize bias. IPCW median OS and hazard ratios (HR) for 2Lm versus AS were estimated with Kaplan-Meier curves and Cox regression models. Results: Overall, 266 BRCAwt pts were included and received niraparib 2Lm (N=123) or were under AS (N=143). Across 2Lm and AS cohorts, prior to cloning and IPCW, 23.6% and 34.3% of pts were aged ≥75 years, and 26.0% and 16.8% had an EHR value for race as other than White, respectively. The majority of pts were from community practice (80.5% and 90.2%, respectively), had serous OC (79.7% and 81.1%) and had Stage III disease (53.7% and 60.8%). Homologous recombination deficiency status was unknown for 92.7% and 86.0% of pts in 2Lm and AS cohorts, respectively. Median follow-up for 2Lm and AS cohorts was 16.8 (Quartile [Q] 1, Q3: 10.4, 28.7) and 10.2 (Q1, Q3: 4.1, 23.7) months, respectively. IPCW median OS was 28.1 (95% confidence interval [CI]: 22.5, 43.2) and 21.5 (95% CI: 14.7, 27.0) months (HR: 0.63 [95% CI: 0.45, 0.88]) for niraparib 2Lm and AS cohorts, respectively and survival rates at 24 months were 58.2% (95% CI: 47.5, 67.6) and 46.1% (95% CI: 33.6, 57.7). Conclusions: This analysis provides real-world data on OS among pts with OC receiving niraparib 2Lm or under AS in the 2L setting following chemotherapy. Funding: GSK study (219306). Editorial support was provided by Fishawack Health, funded by GSK.

Effects of [177Lu] Lu-PSMA-617 on overall survival in TheraP versus VISION randomized trials: An exploratory analysis.

5045 Background: Observed effects on overall survival (OS) differed in the first two randomized trials (RCTs) of [177Lu] Lu-PSMA-617 (LuPSMA) in metastatic, castration-resistant prostate cancer. TheraP randomized participants to LuPSMA or Cabazitaxel (CBZ). In TheraP, the CBZ group (n = 101) included 20 participants who crossed over to LuPSMA, and the LuPSMA group (n = 99) included 32 who crossed over to CBZ. VISION randomized participants to treatment with or without LuPSMA, plus physicians’ choice among protocol-defined treatments, excluding CBZ. Thirty-eight percent of control group participants in VISION had received CBZ prior to randomization. This study investigated explanations for differences in these RCTs in the observed effects of LuPSMA on OS. Methods: Individual participant data (IPD) on survival time from VISION was extracted from published survival curves for comparison with IPD from TheraP. Rank-preserving structural failure time (RPSFT) and inverse probability of censoring weighting (IPCW) were used in TheraP to estimate treatment effects on OS in counterfactual analyses assuming crossover had not occurred in either group, or in both groups. Results: OS was longer in the comparator group of TheraP than the comparator group of VISION (HR: 0.57, 95% CI 0.43 - 0.75) while OS was similar in the LuPSMA groups of VISION and TheraP (HR: 0.92, 95% CI 0.70 - 1.19). No significant differences in OS between the LuPSMA and CBZ groups of TheraP were apparent using counterfactual analyses assuming crossovers had not occurred (No crossover from CBZ: RPSFT HR 0.97, 95% CI 0.62 –1.52, IPCW HR 0.92, 95% CI 0.65-1.32; No crossover from LuPSMA: RPSFT HR 0.97, 95% CI 0.60–1.58, IPCW HR 0.82, 95% CI 0.55–1.24; No crossover from LuPSMA or CBZ: RPSFT HR 0.97, 95% CI 0.53-1.74, IPCW HR 0.82, 95% CI 0.53–1.27). Conclusions: The difference in observed effects of LuPSMA on overall survival in TheraP and VISION are better explained by the use of different comparator treatments in their control groups than by crossovers in TheraP from Cabazitaxel to LuPSMA, or LuPMSA to Cabazitaxel. Clinical trial information: NCT03392428 , NCT03511664 .

Impact of the treatment crossover design on comparative efficacy in EMPOWER-Lung 1: Cemiplimab monotherapy as first-line treatment of advanced non-small cell lung cancer.

In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression. Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring). In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction-the most suitable method based on published guidelines and trial characteristics-produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction. After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.

IPCW approach for testing independence

Here we present a novel inverse probability of censoring weighted (IPCW) adaptation of the Kochar–Gupta (KG) test of independence, in the case of bivariate randomly censored data. Three different censoring schemes are considered: one of the target variables is censored, both targeted variables are censored with the same censoring variable, and both target variables are censored with different censoring variables. The limiting properties of test statistics are explored. In order to compare the tests with a few well-known competitors in terms of powers, several resampling procedures have been utilised to approximate the null distribution. Special attention is dedicated to the comparison with a classical adaptation of the KG test related to the IPCW adaptation of U-statistics.

Age-Dependent Hemorrhage Risk and Obliteration Benefit After Radiosurgery for Brain Arteriovenous Malformation

Because patients with untreated brain arteriovenous malformations (BAVMs) are at variable risks of cerebral hemorrhage and associated mortality and morbidity, it is essential to identify patient populations who benefit most from prophylactic interventions. This study aimed to examine age-dependent differences in the therapeutic effect of stereotactic radiosurgery (SRS) on BAVMs. This retrospective observational study enrolled patients with BAVMs who underwent SRS at our institution between 1990 and 2017. The primary outcome was post-SRS hemorrhage, and the secondary outcomes included nidus obliteration, post-SRS early signal changes, and mortality. To investigate age-related differences in outcomes after SRS, we performed age-stratified analyses using the Kaplan-Meier analysis and weighted logistic regression with the inverse probability of censoring weighting (IPCW). To address significant differences in patient baseline characteristics, we also performed inverse probability of treatment weighting (IPTW) adjusted for possible confounders to investigate age-related differences in outcomes after SRS. A total of 735 patients with 738 BAVMs were stratified by age. Age-stratified analysis using a weighted logistic regression model with IPCW showed a direct correlation between patient age and post-SRS hemorrhage (odds ratio [OR], 95% confidence interval [CI], and P value: 2.20, 1.34-3.63, and .002 at 18 months; 1.86, 1.17-2.93, and .008 at 36 months; and 1.61, 1.05-2.48, and .030 at 54 months, respectively). The age-stratified analysis also showed an inverse relationship between age and obliteration over the first 42 months after SRS (OR, 95% CI, and P value: 0.05, 0.02-0.12, and <.001 at 6 months; 0.55, 0.44-0.70, and <.001 at 24 months; and 0.76, 0.63-0.91, and .002 at 42 months, respectively). These results were also confirmed with the IPTW analyses. Our analysis demonstrated that patients' age at SRS is significantly associated with hemorrhage and the nidus obliteration rate after treatment. In particular, younger patients are more likely to exhibit reduced cerebral hemorrhages and achieve earlier nidus obliteration compared with older patients.

Informative Censoring-A Cause of Bias in Estimating COVID-19 Mortality Using Hospital Data.

(1) Background: Several retrospective observational analyzed treatment outcomes for COVID-19; (2) Methods: Inverse probability of censoring weighting (IPCW) was applied to correct for bias due to informative censoring in database of hospitalized patients who did and did not receive convalescent plasma; (3) Results: When compared with an IPCW analysis, overall mortality was overestimated using an unadjusted Kaplan-Meier curve, and hazard ratios for the older age group compared to the youngest were underestimated using the Cox proportional hazard models and 30-day mortality; (4) Conclusions: An IPCW analysis provided stabilizing weights by hospital admission.

Uniform Consistency for Functional Conditional U-Statistics Using Delta-Sequences

U-statistics are a fundamental class of statistics derived from modeling quantities of interest characterized by responses from multiple subjects. U-statistics make generalizations the empirical mean of a random variable X to the sum of all k-tuples of X observations. This paper examines a setting for nonparametric statistical curve estimation based on an infinite-dimensional covariate, including Stute’s estimator as a special case. In this functional context, the class of “delta sequence estimators” is defined and discussed. The orthogonal series method and the histogram method are both included in this class. We achieve almost complete uniform convergence with the rates of these estimators under certain broad conditions. Moreover, in the same context, we show the uniform almost-complete convergence for the nonparametric inverse probability of censoring weighted (I.P.C.W.) estimators of the regression function under random censorship, which is of its own interest. Among the potential applications are discrimination problems, metric learning and the time series prediction from the continuous set of past values.

Model selection for survival individualized treatment rules using the jackknife estimator

BackgroundPrecision medicine is an emerging field that involves the selection of treatments based on patients’ individual prognostic data. It is formalized through the identification of individualized treatment rules (ITRs) that maximize a clinical outcome. When the type of outcome is time-to-event, the correct handling of censoring is crucial for estimating reliable optimal ITRs.MethodsWe propose a jackknife estimator of the value function to allow for right-censored data for a binary treatment. The jackknife estimator or leave-one-out-cross-validation approach can be used to estimate the value function and select optimal ITRs using existing machine learning methods. We address the issue of censoring in survival data by introducing an inverse probability of censoring weighted (IPCW) adjustment in the expression of the jackknife estimator of the value function. In this paper, we estimate the optimal ITR by using random survival forest (RSF) and Cox proportional hazards model (COX). We use a Z-test to compare the optimal ITRs learned by RSF and COX with the zero-order model (or one-size-fits-all). Through simulation studies, we investigate the asymptotic properties and the performance of our proposed estimator under different censoring rates. We illustrate our proposed method on a phase III clinical trial of non-small cell lung cancer data.ResultsOur simulations show that COX outperforms RSF for small sample sizes. As sample sizes increase, the performance of RSF improves, in particular when the expected log failure time is not linear in the covariates. The estimator is fairly normally distributed across different combinations of simulation scenarios and censoring rates. When applied to a non-small-cell lung cancer data set, our method determines the zero-order model (ZOM) as the best performing model. This finding highlights the possibility that tailoring may not be needed for this cancer data set.ConclusionThe jackknife approach for estimating the value function in the presence of right-censored data shows satisfactory performance when there is small to moderate censoring. Winsorizing the upper and lower percentiles of the estimated survival weights for computing the IPCWs stabilizes the estimator.