Analysis of Censored Survival Data with Intermittently Observed Time-Dependent Binary Covariates

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d620556e60"> <b>Objectives:</b> The Cox proportional hazard model had been used extensively to evaluate time-to-event (TTE) endpoints in drug development. The model assumes that event times are unique and distinct across subjects. When tied times occur, correction methods can be used to minimize bias in parameter estimation. Efron’s correction method is considered a balanced choice between the accuracy of estimate (over Breslow method) and computational intensity (over Exact method) and is used as the default option in R, however, its implementation in NONMEM has not been developed. This method introduces Efron correction in NONMEM for evaluating the effects of time-variant and time-invariant covariates on TTE endpoints in Cox regression. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d620556e65"> <b>Methods:</b> To implement the Cox Regression with Efron Correction in NONMEM, simulation datasets with 500 subjects were created, consisting of a time-variant covariate, a time-invariant covariate, and a TTE response variable. The event times were generated based on a bathtubs-like baseline hazard function and prespecified covariates’ effects on the baseline hazard for the events. Censoring times were generated from a constant hazard. The time records were obtained from either the event time or censoring time, whichever occurred first. The tied-time records were created by rounding up the times to the closest day, week, or month, mimicking scenarios when the time records are collected by day, week, or month. To implement Cox regression in NONMEM, the datasets were rearranged such that the subjects were organized by event/censoring times in descending order. For tied-time records, subjects with tied censoring times arranged before subjects with tied event times. The partial likelihood calculation for Efron correction employed a do-while loop and two variables defined in abbreviation block to facilitate calculations for the numerators and denominators of the partial likelihoods across the events over time. Lastly, model parameters were estimated in NONMEM and R for validation and comparison. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d620556e70"> <b>Results:</b> Tie-time records of 305, 444, and 484 were generated when rounding up the event/censoring times to the nearest day, week, and month, respectively, over 195 distinct days, 56 distinct weeks, and 16 distinct months. Estimated coefficients and the corresponding standard errors for the effects of time-invariant and time-variant covariates were found to be similar between NONMEM and R across all cases, when applying Efron correction in the Cox regression analyses (differences &lt; 0.2%). This indicates that the newly proposed workflow in NONMEM is comparable to R and can be effectively adopted for TTE analysis with tie-records. <p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" dir="auto" id="d620556e75"> <b>Conclusions:</b> The developed NONMEM workflow successfully implements Efron correction for tied-time records in Cox regression. Compared to traditional statistical software, this workflow can be extended to incorporate complex nonlinear time-variant covariates and pharmacokinetic and pharmacodynamic models with ordinary differential equations for TTE analysis, conveniently within NONMEM in the field of pharmacometrics.

Survival analysis is often used to compare experimental and conventional treatments. In observational studies, the therapy may change during follow-up and such crossovers can be summarized by time-dependent covariates. Given the ever-increasing donor organ shortage, higher-risk kidneys from expanded criterion donors (ECD) are being transplanted. Transplant candidates can choose whether to accept an ECD organ (experimental therapy), or to remain on dialysis and wait for a possible non-ECD transplant later (conventional therapy). A three-group time-dependent analysis of such data involves estimating parameters corresponding to two time-dependent indicator covariates representing ECD transplant and non-ECD transplant, each compared to remaining on dialysis on the waitlist. However, the ECD hazard ratio estimated by this time-dependent analysis fails to account for the fact that patients who forego an ECD transplant are not destined to remain on dialysis forever, but could subsequently receive a non-ECD transplant. We propose a novel method of estimating the survival benefit of ECD transplantation relative to conventional therapy (waitlist with possible subsequent non-ECD transplant). Compared to the time-dependent analysis, the proposed method more accurately characterizes the data structure and yields a more direct estimate of the relative outcome with an ECD transplant.

Analysis of ordinal longitudinal data under nonignorable missingness and misreporting: An application to Alzheimer’s disease study

To conduct an assessment of time-dependent covariates related to dental caries of the permanent dentition among a low socioeconomic status, understudied cohort of children, incorporating time-dependent covariates through the application of extended Cox proportional hazards modeling. This study modeled the time to first cavitated dental caries in permanent teeth among school-aged children and assessed factors associated with this event. A cohort of 98 low socioeconomic status African-American children with mean age of 5.85 years at baseline was recruited in Uniontown, Alabama and followed prospectively for 6 years. None of these children had dental caries on permanent teeth at baseline, and oral examinations were performed annually. Caries-free survival curves were generated to describe time to event (having first decayed, filled, or missing permanent surface). Bivariate and multivariable extended Cox hazards modeling was used to assess the relationships between time-dependent and time-independent covariates and time to event. Twenty-eight children (28.6 percent) had their first permanent tooth caries event during the 6-year follow-up. Multivariable results showed that greater consumption of water was associated with lower dental caries hazard, while previous primary tooth caries experience was associated with greater dental caries hazard after adjustment for frequency of consumptions of milk, added-sugar beverages, and 100 percent juice. There was a global/overall significant caries protective effect of water consumption during the school-age period of child development.

Recurrent gap times are analyzed with diverse methods under several assumptions such as a marginal model or a frailty model. Several resampling techniques have been recently suggested to estimate the covariate effect; however, these approaches can be applied with a time-fixed covariate. According to simulation results, these methods result in biased estimates for a time-varying covariate which is often observed in a longitudinal study. In this paper, we extend a resampling method by incorporating new weights and sampling scheme. Simulation studies are performed to compare the suggested method with previous resampling methods. The proposed method is applied to estimate the effect of an educational program on traffic conviction data where a program participation occurs in the middle of the study.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of &lt;i&gt;DAPK3&lt;/i&gt; and &lt;i&gt;METTL6&lt;/i&gt;, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. &lt;i&gt;Clin Cancer Res; 17(17); 5801–11. ©2011 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Thoracic radiotherapy is a primary treatment modality for lung cancer, with approximately two-thirds of patients receiving it. The association between heart dose and post-radiotherapy survival and cardiac injury represents a critical area of contemporary radiotherapy research, yet understanding of radiation-induced heart disease (RIHD) in lung cancer remains incomplete. This review synthesizes literature on the effects of heart dose on survival and substructure-specific cardiac injury in lung cancer patients, evaluating thresholds for reversible and irreversible damage to cardiac substructures. We further summarize key mechanisms underlying RIHD.

Role of B Cell Recovery in Relapse Risk and CD19 Phenotype Following Real-World Use of Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia: A Multi-Institutional Retrospective Study

Urban greenness and survival in lung cancer patients: A registry-based cohort study in Beijing

Survival analyses have been used to overcome some of the limitations encountered with other statistical analyses. Although extended Cox hazard modeling with time-dependent variables has been utilized in several medical studies, it has never been utilized in assessing the complex relationship between mutans streptococci (MS) acquisition (time-dependent covariate) and time to having dental caries (outcome). This study involved secondary analyses of data from a prospective study conducted at the University of Alabama at Birmingham. Low socioeconomic status, African-American preschool children from Perry County, AL, USA (n = 95) had dental examinations at age 1 year and annually thereafter until age 6 years by three calibrated dentists. Salivary MS tests were done at ages 1, 1.5, 2, 2.5, 3, and 4 years. The patterns of and relationship between initial MS detection (time-dependent covariate) and dental caries experience occurrence were assessed, using extended Cox hazard modeling. The median time without MS acquisition (50% of the children not having positive MS test) was 2 years. Approximately 79% of the children had positive salivary MS tests by the age of 4 years. The median caries experience survival (50% of the children not having dental caries) was 4 years. During the follow-up period, 65 of the children (68.4%) had their initial primary caries experience. Results of the extended Cox hazard modeling showed a significant overall/global relationship between initial caries experience event at any given time during the follow-up period and having a positive salivary MS test at any time during the follow-up period (hazard ratio = 2.25, 95% CI 1.06-4.75). In conclusion, the extended Cox modeling was used for the first time and its results showed a significant global/overall relationship between MS acquisition and dental caries. Further research using causal mediation analysis with survival data is necessary, where the mediator “presence of MS” is treated as a time-dependent variable.

The goals in clinical and cohort studies often include evaluation of the association of a time-dependent binary treatment or exposure with a survival outcome. Recently, several impactful studies targeted the association between initiation of aspirin and survival following colorectal cancer (CRC) diagnosis. The value of this exposure is zero at baseline and may change its value to one at some time point. Estimating this association is complicated by having only intermittent measurements on aspirin-taking. Commonly used methods can lead to substantial bias. We present a class of calibration models for the distribution of the time of status change of the binary covariate. Estimates obtained from these models are then incorporated into the proportional hazard partial likelihood in a natural way. We develop non-parametric, semiparametric, and parametric calibration models, and derive asymptotic theory for the methods that we implement in the aspirin and CRC study. We further develop a risk-set calibration approach that is more useful in settings in which the association between the binary covariate and survival is strong.

2601 Background: The impact of kidney immune-related adverse events (KirAEs) and their management (mgmt) on clinical outcomes in patients receiving immune checkpoint inhibitors (ICI) has not been fully examined. We aimed to evaluate the association between KirAEs, their mgmt, and progression-free survival (PFS) and overall survival (OS) in ICI-treated cancer patients. Methods: Data were drawn from the Flatiron Health Research Database, an EHR-based database representing 280+ U.S. oncology practices. Adults with advanced non-small cell lung cancer (aNSCLC), advanced melanoma (aMel), or metastatic renal cell carcinoma (mRCC) who initiated ICI between 1/1/16 - 12/31/20 were included and followed from ICI initiation to death, loss to follow-up, or end of the study period (12/31/21). CTCAE Grade 2 or higher KirAEs and mgmt actions (immunosuppression using corticosteroids or other immunosuppressants, ICI-regimen holds, ICI-regimen discontinuations) and hospitalizations were curated from unstructured data. Cox regression was used to evaluate the association between KirAEs, their mgmt (both as time-varying covariates) and PFS and OS adjusting for baseline characteristics such as line of therapy and corticosteroid use. The earliest KirAE per patient was examined in survival analyses. Results: The study included 513 aNSCLC, 463 aMel, and 451 mRCC patients. For aNSCLC, aMel, and mRCC, respectively, 21.1%, 29.6%, and 33.9% experienced at least one KirAE, with a median time to onset of 70, 84, and 128 days. Nephritis ranged from 2.1% of KirAEs in aNSCLC to 4.6% in aMel. Elevated creatinine was the most common KirAE (23.6% in mRCC to 29.1% in aNSCLC), followed by acute kidney injury (20.5% in mRCC to 28.4% in aNSCLC). Immunosuppression was used to treat KirAEs in 67.6%, 80.3%, and 67.3% of aNSCLC, aMel, and mRCC patients with KirAEs. In aNSCLC, aMel, and mRCC, respectively, median OS was 17.1, 58.6, and 33.7 months, median PFS was 7.8, 8.9, and 9.5 months, and patients with KirAEs had longer PFS than those without KirAEs [HR (95%CI): 0.65 (0.51-0.83); 0.74 (0.57-0.97); 0.67 (0.53-0.84)]. In aNSCLC, KirAEs were associated with shorter OS [1.31 (0.98-1.74); P = 0.06]. In all cancers, KirAEs that occurred during hospitalization or led to hospitalization were associated with shorter OS (HR≥2.84; P &lt; 0.02). KirAE mgmt was not associated with OS or PFS. Conclusions: Results suggest that while KirAEs might indicate an intensified immune response, their management and impact on survival vary across cancer types and call for cancer-specific strategies for early identification and management of KirAEs in the ambulatory care setting.

Inclusion of RBC-Transfusion Dependency Can Improve the Prognostic Value of Revised-IPSS in MDS Patients

THU0235 Identifying and quantifying prognostic factors in systemic sclerosis-related interstitial lung disease using a time-varying covariate survival model

We propose a marginal modeling approach to estimate the association between a time-dependent covariate and an outcome in longitudinal studies where some study participants die during follow-up and both variables have non-monotone response patterns. The proposed method is an extension of weighted estimating equations that allows the outcome and covariate to have different missing-data patterns. We present methods for both random and non-random missing-data mechanisms. A study of functional recovery in a cohort of elderly female hip-fracture patients motivates the approach.